Phytocompounds That Target White Adipose Tissue for Weight Loss: A Review Spanning From Ucp1 Induction in Rodents to Human Clinical Trials

ABSTRACT

Most drugs and supplements for weight loss decrease appetite and food intake, resulting in loss of lean mass and fat mass. An ideal strategy for weight loss would be to directly target adipocytes and stimulate mitochondrial thermogenesis fueled by fatty acid oxidation. Many phytocompounds and food components can act directly on rodent adipocytes to stimulate expression of Ucp1, a mitochondrial protein and marker for thermogenic capacity. Expression of Ucp1 is highly inducible in rodent adipocytes and correlates with lower adiposity after high‐fat diet consumption. The aim of this review is to determine whether the natural compounds that stimulate expression of rodent Ucp1 have the same effect in human adipocytes and translate to reduction of body weight in human clinical trials. Sixteen natural compounds that induce Ucp1 expression in rodent primary adipocytes or adipose tissue were identified from literature searches of PubMed and Web of Science databases. Of these, resveratrol, naringenin, curcumin, menthol, genistein, and artepillin C induce UCP1 in human adipocytes. The most active phytocompounds in human adipocytes bypass receptor signaling and bind nuclear receptors that act on promoter elements to induce thermogenesis genes. Resveratrol, naringenin, curcumin, epigallocatechin‐3‐gallate, fucoxanthin, menthol, provitamin A carotenoids, and capsaicin have been evaluated in clinical trials for weight loss. Naringenin and curcumin stimulate weight loss in multiple clinical trials. Extracts enriched in the active component stimulate greater clinical weight loss than any single active component. We conclude that specific natural compounds that target adipose tissue can stimulate human energy expenditure and meaningful weight loss.

Abbreviations

AMPK

adenosine monophosphate kinase

ArtC

artepillin C

BAT

brown adipose tissue

BC

beta‐carotene

BMI

body mass index

BP

blood pressure

BW

body weight

cAMP

cyclic adenosine monophosphate

CGM

catechins with a galloyl moiety

CKMT1

mitochondrial creatine kinase‐1

CREB

cAMP response element binding protein

EGCG

epigallocatechin‐3‐gallate

FNDC5

fibronectin III domain‐containing protein 5

Fx

fucoxanthin

GTE

green tea extract

HbA1c

hemoglobin‐A1c

HFD

high‐fat diet

HOMA‐IR

homeostatic model assessment of insulin resistance

IS

insulin sensitivity

LDL

low density lipoprotein

MAPK

mitogen‐activated protein kinase

mTOR

mechanistic target of rapamycin

NAFLD

nonalcoholic fatty liver disease

NR

naringenin

NST

nonshivering thermogenesis

OCR

oxygen consumption rate

Pgc‐1α

peroxisome proliferator‐activator receptor coactivator‐1α

PI3K

phosphatidyl inositol 3‐kinase

pK

pharmacokinetic

PM20D1

peptidase M20 domain‐containing‐1

PPAR

peroxisome proliferator‐activator receptor

PRDM16

PR domain‐containing 16

RAR

retinoic acid receptor

REE

resting energy expenditure

RMR

resting metabolic rate

RSV

resveratrol

SIRT1

sirtuin 1

SVF

stromal‐vascular fraction

TG

triglyceride

TGR5

Takeda G protein‐coupled receptor 5

TRPM8

transient receptor potential melastatin 8

TRPV1

transient receptor potential vanilloid 1

UCP1

uncoupling protein 1

WAT

white adipose tissue

WC

waist circumference

β3AR

adrenergic receptor

1. Introduction

The prevalence of obesity has accelerated worldwide as technology has enhanced sedentary behavior and calorie intake has increased [1]. Approximately 59% of the adult population worldwide were overweight or obese in 2022 [2]. There are a number of US Food and Drug Administration (FDA)‐approved drugs currently on the market for obesity treatment, and most target the brain to reduce hunger and food intake [3]. Combined incretin receptor agonists are a new class of obesity therapeutics that can stimulate weight loss of greater than 20% of body weight, more than any previously approved drugs [4]. These drugs act on the gut and brain to reduce hunger, slow digestion, and stimulate insulin secretion [5]. Some of their adverse effects include extreme nausea and loss of lean mass, and their long‐term effects are not yet known [6, 7, 8].

There are no currently available FDA‐approved drugs that reduce body weight by increasing peripheral energy expenditure, despite years of research [3, 9]. There is a great need for obesity therapeutics that target peripheral tissues and can be safely administered long term. A rapidly expanding body of literature indicates that polyphenols and other phytocompounds can reduce or prevent weight gain in rodents on a high‐fat diet (HFD) by activating mitochondrial thermogenesis and fat oxidation in adipose tissues [10, 11, 12, 13, 14].

In rodents, nonshivering thermogenesis can be activated in interscapular brown adipose tissue (BAT), an organ composed of specialized brown adipocyte cells that generate heat to maintain body temperature for survival in the cold. After cold exposure, norepinephrine release into adipose tissues by sympathetic nerves binds β3‐adrenergic receptors (β3ARs) to activate nonshivering thermogenesis. The substantial thermogenic capacity of BAT is facilitated by the presence of uncoupling protein 1 (Ucp1) in mitochondria. High expression of Ucp1 is unique to brown adipocytes and dissipates the mitochondrial proton gradient. This results in uncoupling of ATP synthesis from substrate oxidation and elevated substrate flux through the respiratory chain. Like catecholamines, synthetic β3AR agonists activate nonshivering thermogenesis, increase mitochondrial density, and induce Ucp1 expression in BAT [15, 16]. Human infants have brown adipocytes in the neck and back areas, which help to maintain body temperature. Brown adipocyte numbers decline with age and are barely detectable by adulthood. Based on positron‐emission tomography (PET) imaging, adults with obesity have limited BAT mass, and it is unlikely to sufficiently impact body weight [17].

Interestingly, cold exposure and β3AR agonists can induce Ucp1 expression in rodent white adipose tissue (WAT) [15, 18]. The β3AR signals through a G‐protein‐activated cascade of events involving adenylyl cyclase, cAMP production, protein kinase A, and triglyceride (TG) lipolysis, providing the fatty acids to fuel thermogenesis. Fatty acids are ligands for the nuclear receptors peroxisome proliferator‐activator receptor‐α and ‐γ (PPARα and ‐ƴ), transcriptional activators of Ucp1 and insulin sensitivity genes. The cAMP response element binding protein (CREB) induces multiple mitochondrial thermogenesis genes and substrate cycling pathways in addition to Ucp1, including mitochondrial creatine kinase (CKMT1) and N‐acyl amino acid uncoupling (PM20D1). Ucp1 expression in WAT is highly variable between mouse strains and is influenced by genetics and diet [19, 20]. Based on this variability, multiple studies have shown that Ucp1 expression in WAT positively correlates with resistance to weight gain on a HFD [21, 22, 23]. These discoveries generated strong interest in developing obesity drugs that target β3ARs in human adipose tissues.

Nonshivering thermogenesis is easily inducible in rodents to defend body temperature and is active at ambient indoor temperatures considered comfortable for humans (22°C) [24]. Thermoneutrality for mice (30°C) is important during metabolism experiments to prevent false positives for stimulation of Ucp1 expression and energy expenditure [25]. One could question whether rodent models are suitable for preclinical analysis of therapeutics that target human adipose tissue energy expenditure for weight loss. Efforts to develop a selective human β3AR agonist drug for obesity and diabetes have not been successful over the last several decades [26]. β3AR is expressed at very low levels in human adipose tissue, and β3AR‐targeted drugs have demonstrated little activity in clinical trials and have adverse side effects [27, 28, 29, 30, 31, 32]. We and others have shown that in human adipocytes, the G‐protein‐coupled receptors that stimulate the highest levels of lipolysis, thermogenesis, and UCP1 are the β1AR, atrial natriuretic peptide receptor, and the parathyroid hormone receptor [31, 33, 34]. Because these receptors are expressed in many tissues, they are not utilizable for drugs targeting adipose tissue.

Whereas UCP1 expression is one specific marker for beige adipocytes, functional reprogramming of fat‐storing adipocytes into thermogenically active cells requires upregulation of many genes other than UCP1 including TG lipases, glucose and fatty acid metabolism enzymes, transporters, and mitochondrial uncoupling [35]. In human adipocyte cultures, synthetic ligands for PPARα and PPARγ are some of the strongest documented activators of these genes [36, 37]. Thiazolidinediones (TZDs) are pharmaceutical PPARγ ligands with insulin‐sensitizing activity, and they have been approved by the FDA for the treatment of type‐2 diabetes. However, PPARγ also functions as a master transcriptional regulator of adipogenesis, and one of the side effects of TZD administration in clinical studies is weight gain [38]. Selective PPARγ modulators (SPPARγMs) are partial agonists that have recently gained interest due to their capability to activate the expression of metabolism genes without upregulating adipogenesis [39]. Dual PPARα/ƴ activators also stimulate enhanced adipocyte browning without adipogenesis [40, 41]. Some of the phytonutrients in dietary supplements and foods have been identified as PPARγ ligands or dual PPARα/γ agonists [42, 43, 44]. A subset of these phytonutrients stimulate Ucp1 expression in rodent WATs and reduce weight gain caused by HFD [45, 46].

The aim of this review is to identify phytocompounds that have potential as human anti‐obesity therapeutics via direct effects on WAT fat oxidation and energy expenditure. A literature search of PubMed and Web of Science indexed journals was conducted using the following terms: (Ucp1 OR thermogenesis) AND (adipocyte OR adipose) AND (phytochemical OR polyphenol OR natural compound OR phytonutrient). We limited this review to the induction of Ucp1 as the key indicator for the browning of primary adipocytes or WAT, and 16 bioactive compounds were identified using this search strategy. Only single compounds rather than extracts were included in the search because individual active components must be identified for the standardization of supplements and plant extracts.

All phytocompounds in this review have been evaluated in human cells for UCP1 induction, and some have been tested in multiple clinical trials that measured pharmacokinetics (pK), obesity, energy expenditure, or insulin resistance. Based on these comprehensive data, we highlight key characteristics for predicting clinical efficacy for weight loss. Identification of phytochemicals with potential to target energy expenditure in peripheral tissues is an important first step in formulating safe, long‐term treatments for obesity and diabetes.

2. Results

Sixteen natural compounds sourced from plants and foods stimulate Ucp1 expression in rodent adipose tissue, and the physiological mechanisms have a strong β‐adrenergic component [14]. All compounds have been tested in human white adipocytes. The phytocompounds that induce UCP1 in both rodent and human adipocytes are described in Table 1a, and the compounds that are only active in rodents are in Table 1b. Resveratrol (RSV), epigallocatechin‐3‐gallate (EGCG), fucoxanthin (Fx), menthol, retinoic acid (RA), capsaicin, curcumin, and naringenin (NR) have been tested in multiple clinical trials, and these data are summarized in Table 2 and discussed in the section for each phytocompound.

TABLE 1a.

Phytonutrients that stimulate UCP1 expression in rodent and human adipocytes.

Phytonutrient	Rodent model/cell type	Dose/duration	Effect (mechanism)	References
Resveratrol: Rodent	Db/db mice	Dietary 0.4% for 10 weeks	WAT ↑UCP1, ↓glucose, ↓insulin, no effect BW, ↓microbiota dysbiosis	Hui et al. 2020 [47]
	HFD‐induced obese mice	Dietary 0.4% for 4 weeks	WAT ↑UCP1 ↑SIRT1 ↑PPARƴ, ↓glucose, ↓BW, ↓microbiota dysbiosis	Liao et al. 2018 [48]
	FVB/N mice	Dietary 0.4% for 8 weeks	sWAT ↑UCP1 ↑SIRT1 ↑FNDC5, ↓glucose, ↓insulin, no effect BW	Andrade et al. 2019 [49]
	FVB/N mice	50 μM for 12 h	iWAT and vWAT ↑UCP1, SIRT1 mechanism	Andrade et al. 2019 [49]
Resveratrol: Human	sWAT adipocyte from SVF	50 μM for 12 h	↑UCP1 and ↑SIRT1	Andrade et al. 2019 [49]
Naringenin: Rodent	sWAT tissue and sWAT adipocytes from SVF	10 μM for 14 days during differentiation	↑UCP1 in sWAT and adipocytes, PPAR‐γ mechanism	Bae et al. 2022 [45]
Naringenin: Human	sWAT tissue and adipocytes from SVF	8 μM for 7 or 14 days	↑UCP1, ↑EE in mature adipocytes, AMPK activation, PPAR‐γ/PPAR‐α mechanism	Rebello et al. 2019 [50]
	Rat iWAT adipocytes	1, 10, and 20 μM for 6–8 days	↑Ucp1, ↑PPARγ, ↑AMPK activity	Lone et al. 2016 [51]
Curcumin: Rodent	C57BL/6	50 or 100 mg/kg/day for 50 days	iWAT ↑Ucp1 and ↑β3‐AR, ↑sympathetic activity, ↓BW	Wang et al. 2015 [52]
	Postnatal 3 to 13‐week overfed rats	Dietary 2% for 10 weeks	sWAT ↑Ucp1 and ↑β3‐AR, ↑EE, ↓BW	Zhu et al. 2021 [53]
	C57BL/6J on HFD	Dietary 0.2% for 10 weeks	iWAT ↑Ucp1, ↑EE, ↓BW, ↑IS	Zou et al. 2021 [54]
	CD‐1 mice	Dietary 0.1% for 24 weeks	iWAT ↑Ucp1, ↑TGR5, ↑cAMP	Chen et al. 2025 [55]
Curcumin: Human	sWAT adipocytes from three donor's SVF	10 μM for 7 days	↑UCP1 in 2 of 3 cultures	Coulter et al. 2025 [56]
Menthol: Rodent	C57B1/6J mice on HFD	1% in HFD for 12 weeks	sWAT ↑UCP1, ↓BW, TRPM8/PKA mechanism	Jiang et al. 2017 [57]
	sWAT adipocytes	100 μM for 4 h	↑UCP1, ↑PGC‐1α, ↑β3AR	Jiang et al. 2017 [57]
Menthol: Human	sWAT adipocytes from SVF	1 μM for 24 h	↑UCP1, TRPM8 activation	Rossato et al. 2014 [58]
Genistein: Rodent	C57BL/6 mice, SVF adipocytes	0.2% in HFD with sucrose for 60 days	↑UCP1, ↑PCG‐1α, ↑EE, ↓fat mass	Vásquez‐Reyes et al. 2022 [59]
	C57BL/6J mice, iWAT	30 mg/kg/day by gavage for 10 weeks	↑UCP1, ↑PCG‐1α, no effect BW	Li et al. 2022 [60]
	C57BL/6J mice, eWAT and scWAT	40 mg/kg/day by gavage for 5 days	↑UCP1, ↑PCG‐1α, no effect BW	Fuentes‐Romero et al. 2023 [61]
	C57BL/6 mice, sWAT	0.2% in casein diet for 60 days	↑UCP1, ↑PCG‐1α, AMPK activation, no effect BW	Palacios‐González et al. 2019 [62]
Genistein: Human	SVF adipocytes during adipocyte differentiation	20 μM for 10 days with 0.5‐M IBMX	↑UCP1, ↑PCG‐1α	Rodriguez‐López et al. 2021 [63]
Artepillin C: Rodent	C56BL/6J mice, iWAT	10 mg/kg daily for 4 weeks by gavage	↑Ucp1, PPARγ and PRDM16 mechanism	Nishikawa et al. 2016 [46]
	C56BL/6J mice, iWAT	10 mg/kg daily for 4 weeks by gavage	↑Ucp1, ↑CKMT2, ↑EE	Nishikawa et al. 2020 [64]

Artepillin C: Human

sWAT adipocytes from three donor's SVF

10 μM for 7 days

↑UCP1, ↑CKMT1, ↑PM20D1

Coulter et al. 2025 [56]

Abbreviations: AMPK, adenosine monophosphate kinase; BMI, body mass index; BW, body weight; cAMP, cyclic adenosine monophosphate; CKMT1, mitochondrial creatine kinase‐1; CKMT2, mitochondrial creatine kinase; EE, energy expenditure; FNDC5, fibronectin III domain‐containing protein 5; HFD, high‐fat diet; IS, insulin sensitivity; mTOR, mechanistic target of rapamycin; PKA, protein kinase A; PM20D1, peptidase M20 domain‐containing‐1; PPAR, peroxisome proliferator‐activator receptor; PRDM16, PR domain‐containing 16; SIRT1, sirtuin 1; TGR5, Takeda G protein‐coupled receptor 5 bile receptor; TRPM8, transient receptor potential melastatin 8; UCP1, uncoupling protein 1; WAT, white adipose tissue; β3AR, adrenergic receptor.

TABLE 1b.

Phytonutrients that induce Ucp1 expression in rodent and not in human adipocytes.

Phytonutrient	Mouse model	Dose/duration	Effect (mechanism)	References
Epigallocatechin‐3‐gallate: Rodent	Adipocytes from iWAT SVF	20 μM for 8 days	↑UCP1 and ↑PGC‐1α, AMPK activation	Mi et al. 2018 [65]
Epigallocatechin‐3‐gallate: Human	Adipocytes from SVF	1 μM for 7 days	No effect UCP1 mRNA or lipolysis	Chatree et al. 2021 [66]
Fucoxanthin: Rodent	KK‐Ay mice fed HFD	Dietary 0.4% Fx for 4 weeks	↑UCP1 in WAT, ↓WAT weight	Maeda et al. 2005 [67]
	Obese/diabetic KK‐AY mice	Dietary 0.2% Fx, or 0.1% Fx with 6.9% fish oil for 4 weeks	↑UCP1 ↓TNFα in WAT, ↓blood glucose and insulin levels, ↓WAT weight	Maeda et al. 2007 [68]
	Mice with diet‐induced obesity fed HFD	Dietary 0.05% Fx and 0.2% Fx for 6 weeks	0.2% Fx: ↓BW, 0.05% Fx: ↑UCP1 and ↑adiponectin in eWAT, ↓BW	Woo et al. 2009 [69]
	Wistar rats on 21% HFD	Intragastric 1 mg/kg/day for 8 weeks	↑UCP1 ↑adiponectin ↑PPARƴ in rWAT	Grasa‐López et al. 2016 [70]
Fucoxanthin: Human	Adipocytes from SVF	1 μM for 6 days	No effect on sWAT UCP1 or EE, ↑lipolysis	Rebello et al. 2017 [71]
Quercetin: Rodent	C57BL/6 on HFD	Dietary 0.05% in HFD for 9 weeks	iWAT ↑Ucp1 and ↑β3‐AR, ↑sympathetic activity, no effect BW	Choi et al. 2018 [72]
	C57BL/6 on HFD	Dietary 0.1% for 12 weeks	sWAT ↑Ucp1, ↓plasma TGs, no effect: BW, food intake, or EE	Kuipers et al. 2018 [73]
Quercetin: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]
Capsaicin: Rodent	WT and TRPV1(‐/‐) mice	HFD with 0.1% for 36 weeks	↑UCP1 in eWAT and iWAT, ↓BW, requires activation of TRPV1, SIRT1, and AMPK	Baskaran et al. 2016 [74]
Capsaicin: Human	Mesenchymal stem cells differentiated into adipocytes	25 μM for 3 weeks during differentiation	↓UCP1	Takeda et al. 2022 [75]
Vitamin A/RA: Rodent	Adipocytes from mouse embryonic fibroblasts	1‐μM RA for 24 h	↑UCP1, RAR activation	Murholm et al. 2013 [76]
	Adipocytes from mouse embryonic fibroblasts	0.1‐ and 1‐μM RA for 24 h	↑UCP1, p38MAPK mechanism	Mercader et al. 2010 [77]
Vitamin A/RA: Human	sWAT adipocytes from SVF	10 μM for 14 days	Inhibited differentiation to adipocytes	Murholm et al. 2013 [76]
	sWAT adipocytes from SVF	1‐μM RA for 24 h	No effect on UCP1	Murholm et al. 2013 [76]
	sWAT adipocytes from SVF	2‐μM BC for 7 days	No effect on UCP1	Coulter et al. 2023 [31]
Apigenin: Rodent	C57BL/6 on HFD	12‐week dietary 0.04% for 12 weeks	WAT ↑Ucp1 and ↑Pgc‐1α, ↓BW, ↑EE, ↑lipolysis, ↑fat oxidation, ↑NST, ↑IS	Sun et al. 2019 [78]
Apigenin: Rodent	Adipocytes from C57BL/6 on HFD	50 μM for 48 h	↑Ucp1, ↑EE, ↓TG accumulation, ↑PI3K‐Akt‐mTOR pathway	Xiong et al. 2023 [79]
	Obese C57BL/6 on HFD	Dietary 0.1 mg/g for 4 weeks	↓BW, ↓WAT weight, ↑NST, ↑IS	Xiong et al. 2023 [79]
Apigenin: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]
Luteolin: Rodent	C57BL/6 on HFD	12‐week dietary 0.01%	sWAT ↑Ucp1 and ↑Pgc‐1α, ↓BW, ↑EE	Zhang et al. 2016 [80]
	Primary sWAT adipocytes	100 nM for 24 h	↑Ucp1, ↑Pgc‐1α, ↑AMPK activity	Zhang et al. 2016 [80]
Luteolin: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]
Berberine: Rodent	Db/db mice, iWAT adipocytes	0.5 and 2.5 mM for 24 h	↑Ucp1, ↑ PGC‐1α	Zhang et al. 2014 [81]
	Obese db/db mice	IP injection 5 mg/kg every 3 days for 4 weeks	iWAT ↑Ucp1, ↑Pgc‐1α, and ↑AMPK, ↑EE, ↑NST, ↑IS, ↓BW	Zhang et al. 2014 [81]
Berberine: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]
Kaempferol: Rodent	C57BL/6J on HFD	25, 50, or 100 mg/kg/day by gavage for 14 weeks	iWAT ↑Ucp1 and ↑Pgc‐1α, ↑EE, ↓BW, IS↑	Zhang et al. 2023 [82]
Kaempferol: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]
Myricetin: Rodent	Db/db mice	400 mg/kg by gavage 14 weeks	iWAT ↑Ucp1 ↑EE, ↑IS, ↓BW	Hu et al. 2018 [83]
	C57BL/6J on HFD	10 mg/kg/day by IP 2 weeks	No change in WAT Ucp1, ↑EE, ↓BW, ↓serum TG, ↑IS	Akindehin et al. 2018 [84]
Myricetin: Human	sWAT adipocytes from SVF of three donors with obesity	10 μM for 7 days	No effect on UCP1	Coulter et al. 2025 [56]

Abbreviations: AMPK, adenosine monophosphate kinase; BW, body weight; cAMP, cyclic adenosine monophosphate; EE, energy expenditure; HFD, high‐fat diet; IS, insulin sensitivity; MAPK, mitogen‐activated protein kinase; mTOR, mechanistic target of rapamycin; NST, nonshivering thermogenesis; Pgc‐1α, peroxisome proliferator‐activator receptor coactivator‐1α; PI3K, phosphatidyl inositol 3‐kinase; RAR, retinoic acid receptor; SIRT1, sirtuin 1; SVF, stromal‐vascular fraction; TG, triglyceride; TRPV1, transient receptor potential vanilloid 1; UCP1, uncoupling protein 1; WAT, white adipose tissue; β3AR, adrenergic receptor.

TABLE 2.

Clinical trial outcomes for phytocompounds and enriched extracts.

Compound	Design	Participants	Duration	Intervention	Outcomes	References
Resveratrol	Randomized, double‐blind, placebo‐controlled	Men/women with overweight	6 months	150 mg/day	No effect on BW, insulin, or glucose	de Ligt et al. 2020 [85]
	Randomized, double‐blind, placebo‐controlled crossover	Men with obesity	30 days	150 mg/day	No effect on BW, ↓glucose, ↓insulin	Timmers et al. 2011 [86]
	Randomized, double‐blind, placebo‐controlled	Healthy men with obesity	4 weeks	500 mg 3×/day	No effect on BW, glucose, insulin, HomaIR, or HbA1c	Poulsen et al. 2013 [87]
	Randomized, double‐blind, placebo‐controlled	Men/women with metabolic syndrome	90 days	500 mg 3×/day with isocaloric diet and nutrition therapy	↓BW 3.9 kg, ↓fat mass, ↓WC, ↓insulin	Mendez‐del Villar et al. 2014 [88]
	Randomized, double‐blind, placebo‐controlled	Men with metabolic syndrome	16 weeks	500 mg 2×/day	No effects on BW, fat mass, insulin, or glucose	Kjær et al. 2017 [85]
	Randomized, sequential, placebo‐controlled	Men/women with obesity	28 days	150 mg/day	No effect on antioxidant enzymes	De Groote et al. 2012 [89]
Resveratrol—Grape seed extract	Randomized, sequential, placebo‐controlled	Healthy men/women with obesity	28 days	400‐mg/day catechin‐rich GSE, 300‐mg/day RSV triphosphate	↑glutathione peroxidase, ↑total systemic antioxidant power	De Groote et al. 2012 [88]
Epigallocatechin‐3‐gallate	Randomized, double‐blind, placebo‐controlled	Men/women with obesity	8 weeks	150 mg 2×/day	No effect on body weight, fat mass, glucose, insulin	Chatree et al. 2021 [66]
	Randomized, double‐blind, placebo‐controlled	Postmenopausal women with obesity or overweight	12 weeks	150 mg 2×/day with exercise	No significant differences from placebo	Hill et al. 2007 [90]
	Randomized, placebo‐controlled, double‐blind crossover	Men with overweight or obese	3 days	Daily 300, 600, 300 + 200, or 200‐mg caffeine	No effect on energy expenditure	Thielecke et al. 2010 [91]
	Randomized, double‐blind, placebo‐controlled	Premenopausal women with obesity	12 weeks	300 mg/day	No effect on body weight, fat mass, adiposity, glucose, insulin	Mielgo‐Ayuso et al. 2014 [92]
EGCG—Green tea extract	Double‐blind	Healthy males	12 weeks	690‐mg/day catechins with 75‐mg caffeine	↓BW 1.5%, ↓fat mass, ↓WC	Nagao et al. 2005 [93]
	Double‐blind, parallel, multicenter trial	Men/women with obesity	12 weeks	583‐mg/day GTE	↓BW 1.7 kg, ↓fat mass, ↓WC, ↓systolic BP	Nagao et al. 2007 [94]
	Randomized, double‐blind, placebo‐controlled	Men/women with obesity	12 weeks	180 and 280 mg/day with CGM catechins	280‐mg dose ↓BW 0.5 kg, ↓vWAT, ↓sWAT	Kobayashi et al. 2016 [95]
	Randomized, placebo‐controlled	Men/women overweight	90 days	30 and 458 mg daily, or 2×/day: 30, 468g, or 886 mg	886‐mg dose ↓BW 1.2 kg, ↓abdominal WAT	Wang et al. 2010 [96]
	Randomized, double‐blind, placebo‐controlled	Women with obesity	12 weeks	857‐mg/day GTE decaffeinated	↓BW 1.1 kg, ↓WC, ↓cholesterol	Chen et al. 2016 [97]
	Randomized, double‐blind, placebo‐controlled	Postmenopausal women with obesity or overweight	60 days	150‐mg GTE 2×/day	↓WC, ↓fat mass, ↑fat oxidation, ↑REE, ↓RQ, ↓insulin	Rondanelli et al. 2022 [98]
	Randomized, double‐blind, placebo‐controlled	Women with obesity	12 weeks	400 mg 3×/day GTE	No effect on BW or WC	Hsu et al. 2008 [99]
	Randomized, parallel‐arm, double‐blind, placebo‐controlled	Postmenopausal females that are overweight or obese	12 months	843‐mg/day GTE	No effect on adiposity, FFM, or bone mineral density	Dostal et al. 2016 [100]
	Double‐blind, placebo‐controlled, parallel design	Women with overweight	32 days	1125‐mg/day catechins with 225‐mg caffeine	No effects on BW	Diepvens et al. 2005 [101]
	Randomized, placebo‐controlled	Men/women with obesity or normal weight	12 weeks	560‐mg/day GTE	No effect on BW, REE, or fat oxidation	Janssens et al. 2015 [102]
Fucoxanthin	Randomized, placebo‐controlled	Men/women with obesity or normal weight	8 weeks	1 or 2 mg/day	No effect on vWAT area or REE, ↓HbA1c	Mikami et al. 2017 [103]
	Randomized, double‐blind, placebo‐controlled	Men/women with metabolic syndrome	12 weeks	12 mg/day	↓BW 1.4 kg, ↓WC, ↓BP, ↓TG	López‐Ramos et al. 2023 [104]
	Randomized, double‐blind, placebo‐controlled	Premenopausal women obese, nondiabetic with or without NAFLD	16 weeks	Fx 1.6, 2.4, 4, and 8 mg 3×/day	2.4, 4, and 8 mg ↑REE in NAFLD, BW not measured	Abidov et al. 2010 [105]
Fucoxanthin—Seaweed extract (Xanthigen)	Randomized, double‐blind, placebo‐controlled	Premenopausal women obese, nondiabetic with or without NAFLD	16 weeks	Xanthigen with Fx 1.6, 2.4, or 4 mg 3×/day	↓BW 5.5 kg, ↓WC, ↓body fat, ↓liver fat, ↑REE in NAFLD group	Abidov et al. 2010 [105]
Menthol	Randomized, double‐group	Healthy men/women	2 days	Oral 10 mg/kg	↑10% metabolic rate	Valente et al. 2015 [106]
	Randomized, double‐group	Healthy men/women	2 days	Topical 10 mg/kg	↑18% metabolic rate	Valente et al. 2015 [58]
Vitamin A/RA (mixed carotenoids)	Randomized, double‐blind, placebo‐controlled intervention	Male/female children with obesity	6 months	Mixed carotenoid supplement	↓BMI z‐score, ↓waist‐to‐height ratio, ↓subcutaneous adipose tissue	Canas et al. 2017 [107]
	Randomized, double‐blind, controlled	Men with overweight	8 weeks	Mixed carotenoid diet	↓vWAT	Takagi et al. 2020 [108]
	Cross‐sectional population study	Men/women	5 years	Serum carotenoids	Inverse correlation with visceral fat index, TG, HDL	Yan et al. 2023 [109]
Capsaicin	Randomized, double‐blind, placebo‐controlled	Healthy men/women	12 weeks	2 or 4 mg/day	No effect on IS or body composition	Urbina et al. 2017 [75]
Curcumin	Randomized, double‐blind, placebo‐controlled	Men/women with prediabetes	9 months	1.5 g/day	↓BW 3.9 kg, ↓HOMA‐IR	Chuengsamarn et al. 2012 [ 110 ]
	Randomized, double‐blind, placebo‐controlled	Men/women with obesity	30 days	1 g/day	No effect BMI or body fat	Mohammadi et al. 2013 [56]
	Randomized, double‐blind, placebo‐controlled	Men/women with T2D	10 weeks	1.5 g/day	↓BW 0.6 kg, ↓fasting glucose	Hodaei et al. 2019 [111]
	Randomized, double‐blind, placebo‐controlled	Men/women with NAFLD	12 weeks	1.5 g/day with diet and exercise	↓BW 2.4 kg, no difference from placebo group	Saadati et al. 2019 [112]
	Randomized, double‐blind, placebo‐controlled	Men/women with T2D and MASLD	12 months	1.5 g/day	↓BMI, fasting glucose, liver stiffness	Yaikawawong et al. 2025 [113]
	Randomized, double‐blind, placebo‐controlled	Men/women with overweight	30 days	1.6 mg with piperine/day	↓BW 5%	Di Pierro et al. 2015 [114]
Naringenin	Randomized, double‐blind, placebo‐controlled	Men/women overweight/obese with NAFLD	4 weeks	100 mg 2×/day	↓BMI, ↓vWAT weight, ↓systolic BP, ↓TG, ↓LDL	Naeini et al. 2022 [116]
	Randomized, double‐blind, placebo‐controlled, parallel	Men/women overweight/obese with NAFLD	4 weeks	100 mg 2×/day	↓BW 2.5 kg, ↓WC, ↓blood markers of NAFLD	Namkhah et al. 2021 [117]
Naringenin orange extract	Case study	Woman with obesity and diabetes	8 weeks	150 mg 3×/day	↓BW 2.3 kg, ↑RMR, ↑HOMA‐IR	Murugesan et al. 2020 [43]

Abbreviations: BMI, body mass index; BP, blood pressure; BW, body weight; CGM, catechins with a galloyl moiety; Fx, fucoxanthin; GSE, grape seed extract; EGCG, epigallocatechin‐3‐gallate; GTE, green tea extract; HbA1c, hemoglobin‐A1c; HOMA‐IR, homeostatic model assessment of insulin resistance; IS, insulin sensitivity; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; REE, resting energy expenditure; RMR, resting metabolic rate; TG, triglyceride; WAT, white adipose tissue; WC, waist circumference.

2.1. Six Phytocompounds Induce UCP1 in Both Rodent and Human Adipocytes

RSV, NR, curcumin, menthol, genistein, and artepillin C (ArtC) induce UCP1 expression in human adipocytes (Table 1a). Importantly, the first four of these active phytocompounds have been tested in clinical trials for effects on weight loss, insulin sensitivity, or energy expenditure (Table 2).

2.1.1. RSV

RSV (3,5,40‐trihydroxy‐trans‐stilbene) is enriched in grapes, berries, and peanuts and is present at low levels in wine and grape juice [118]. Orally administered RSV has limited bioavailability. Although 70% is absorbed, most RSV is rapidly converted to inactive metabolites. Multiple human pK studies have reported that only trace amounts of RSV can be detected in human plasma, even after a daily dose as high as 2 g [119, 120, 121, 122]. In contrast, one human safety and pK trial reported detectable levels of RSV in serum after high doses of 2.5 and 5 g daily, and doses over 1 g caused gastrointestinal side effects [123].

The ability of RSV to prevent adiposity associated with an HFD has been documented in mice, but the effects vary between strains (Table 1a). In db/db (diabetic) mice, a chow diet supplemented with 0.4% RSV for 10 weeks stimulated Ucp1 expression in inguinal WAT with no change in body weight [47]. An HFD supplemented with 0.4% RSV for 8 weeks in C57B6/6J mice induced expression of Ucp1 in inguinal and perigonadal WAT and prevented HFD‐induced gains in body weight [48]. Both studies showed beneficial effects of RSV on gut microbiota.

Andrade et al. looked at the effects of RSV in mice on an HFD, in human primary adipocyte cultures, and in human fat biopsies from subjects who had taken oral RSV daily for 8 weeks (Table 1a). After ingesting an HFD with 0.4% RSV for 8 weeks, FVN/B mice had small increases in Ucp1, SIRT1, and fibronectin type III domain‐containing protein 5 (FNDC5) in WAT and normalized circulating glucose and insulin levels compared to HFD alone [49]. There was no change in body weight, but the mass of visceral WAT and subcutaneous WAT decreased in mice. In the same study, treatment of primary human adipocyte cultures with 50‐μM RSV for 12 h induced a small increase in UCP1 and SIRT1, and the effect was eliminated by a SIRT1 inhibitor [49]. However, since RSV is almost undetectable in human serum after consumption of a dose of 2 g, 50 μM is not a physiologically achievable concentration. Twenty subjects with body mass index (BMI) > 30 kg/m² were randomized to RSV 500 mg/day or placebo, and fat biopsies were evaluated for changes in UCP1 and SIRT1 gene expression. Compared to the placebo group, there was a small but significant elevation in UCP1, SIRT1, and FNDC5 after 8 weeks [49]. The secreted portion of FNDC5, known as irisin, can drive thermogenesis in mice, but the role of irisin in humans is not clear [124].

To study the effects of RSV on weight loss in individuals with obesity, multiple clinical trials have been conducted using a range of doses (Table 2) [125]. In two placebo‐controlled, double‐blinded trials that administered 150 mg of RSV daily, there were no effects on body weight, even in the 6‐month trial [86, 126]. A large, double‐blinded, placebo‐controlled trial was conducted in 66 men with obesity who were administered 500 mg of RSV twice daily for 16 weeks. The data showed that RSV treatment had no effect on circulating insulin or glucose levels, or on body composition measured by dual energy x‐ray absorptiometry (DXA) [85]. Two high‐dose clinical trials tested 1500 mg of RSV per day, given in three 500‐mg doses. In the shorter duration, 4‐week trial conducted in Denmark, RSV or placebo was administered to 24 healthy male subjects with mean BMI > 30 kg/m² who were asked to maintain a normal lifestyle. There were no significant differences between groups in BMI, TG, fasting insulin, or glucose [87]. The other RSV trial was conducted for 90 days in Mexico in 24 subjects with a mean BMI > 33 kg/m² using a blinded, placebo‐controlled design. All subjects were given nutrition therapy with an isocaloric diet containing at least 250 g of carbohydrates to stimulate insulin secretion [88]. Mean body weight was reduced by 3.9 kg (p < 0.01) in the RSV‐treated group compared to the placebo group [88]. Additionally, there were reductions in insulin and fat mass [88]. The weight loss in this study has not been replicated in any other clinical trial.

RSV may have better efficacy if chemically altered in a manner that would slow its metabolism. RSV triphosphate is a stable derivative which was compared to equimolar amounts of RSV at 150 mg/day and catechin‐rich grape seed extract in a clinical trial. In 32 individuals with obesity, all subjects were given placebo for 28 days to determine baseline variation in biochemical markers evaluated in the study. Subjects were then randomized to the three treatments for 28 days in a three‐arm trial to evaluate changes in markers of oxidative stress [89]. Analysis of total antioxidant power in plasma samples showed that the RSV group was unchanged, the catechin‐rich grape seed extract group was higher than baseline, and the RSV triphosphate group was significantly higher than both other groups [89]. In summary, the RSV clinical data suggests that effects of RSV on weight loss are limited by its rapid metabolism and low bioavailability.

2.1.2. NR

NR is an active metabolite of naringin, and both compounds are safe, highly bioavailable flavonoids that are enriched in citrus fruit peel and pulp. After consumption, naringin is converted to NR by gut bacteria before absorption in the GI tract [127]. A human pK study demonstrated that mean serum concentrations of NR reach 15 μM after a 150‐mg dose and plateau at approximately 48 μM after a 600‐ or 900‐mg dose [128]. NR is a dual PPARα and PPARƴ activator and stimulates thermogenic gene expression in human hepatocytes and adipocytes [44, 50, 129].

In vivo mouse models have shown that addition of NR to the diet lowers adiposity, increases energy expenditure, and preserves muscle mass in ovariectomized mice [130, 131]. In primary mouse pre‐adipocytes from subcutaneous WAT and epididymal WAT, addition of 10‐μM NR during differentiation increased Ucp1 twofold, and in mature adipocytes, NR enhanced βAR agonist‐stimulated Ucp1 levels [45].

Rebello et al. demonstrated that 8‐μM NR treatment of human adipocytes increased energy expenditure (basal and maximal oxygen consumption rate [OCR]), AMPK activation, and expression of UCP1 and TG lipase [50]. Similar effects were observed in adipocyte cultures as well as in surgically removed adult fat treated with NR [50]. In another study in human adipocytes, treatment with a Citrus sinensis orange extract standardized to 30% NR was more potent than the equivalent of pure NR. Addition of 2‐μM BC to the extract (NRBC) further increased expression of UCP1 and additional genes for thermogenesis and insulin sensitivity, including CKMT1, PM20D1, and adiponectin [31]. Importantly, NRBC treatment for 7 days upregulated levels of lipolytic receptors, including all βARs, parathyroid hormone receptor, and natriuretic peptide receptor, and enhanced agonist‐stimulated lipolysis [31]. These receptor effects suggest that sensitivity of adipocytes to circulating thermogenic hormones released after eating, exercise, and cold exposure would be higher in individuals taking NRBC supplements [33, 117, 132].

NR has been evaluated for weight loss in a blinded, placebo‐controlled clinical trial in which 100 mg was administered twice a day to 44 individuals with obesity and NAFLD. After 4 weeks of supplementation, body weight decreased by 2.5 kg (p < 0.002) compared to placebo, and reductions in abdominal fat, low density lipoprotein, and TG were observed [116, 133]. In a case study of a sedentary woman with obesity and diabetes, body weight, insulin sensitivity, and energy expenditure were measured after 8 weeks of supplementation with an orange extract standardized to 150 mg of NR taken three times daily. At the end of the study, body weight was 2.3 kg (2.1%) lower, TG and insulin were reduced, and resting energy expenditure was elevated [44]. Considering that NR is bioavailable and can reach approximately 45 μM in human serum after a 600‐mg dose, the clinical data from low‐dose treatments indicate potential for higher weight loss with higher doses and coadministration with BC [128].

2.1.3. Curcumin

Curcumin is the active ingredient of the traditional Asian spice known as turmeric. It has been actively researched for many years for its strong antioxidant and anticancer activities. In mouse and rat models of HFD‐induced obesity, dietary supplementation with curcumin increases β3AR activity, reduces weight gain, upregulates Ucp1 expression in WAT, and stimulates energy expenditure and insulin sensitivity (Table 1a) [51, 52, 53, 54, 55].

Coulter et al. examined the effects of curcumin and multiple other phytocompounds on UCP1 expression in human adipocyte cultures, and 10‐μM NR was included in the study as a positive control for UCP1 induction [56]. Adipocytes were differentiated from the stromal vascular fraction (SVF) of subcutaneous adipose tissue from women and men with obesity. Adipocytes were then treated for 7 days with 10‐μM curcumin, 10‐μM NR, and other phytocompounds in medium with heat‐inactivated fetal bovine serum to minimize hormone effects, described in previous studies [31, 50]. Compared to untreated controls, curcumin increased UCP1 mRNA fivefold and threefold in two of the cultures, had no effect in the third, and NR induced UCP1 at least 12‐fold in all cells [56].

Multiple blinded, placebo‐controlled clinical trials have measured the effects of curcumin on weight loss or BMI (Table 2). Administration of 1‐g/day curcumin for 30 days to subjects with obesity had no effect on BMI or body fat [110]. In four studies in which subjects consumed at least 1.5 g of curcumin daily for 12 weeks or more, body weight and BMI were reduced and insulin sensitivity improved [111, 112, 113, 134]. Weight loss of 3.9 kg (p < 0.05) with improvements in insulin sensitivity was achieved in a 9‐month blinded, placebo‐controlled trial that administered 1.5 g/day of curcumin [113]. The efficacy of curcumin is hindered by poor solubility in water and poor intestinal absorption. Addition of piperine increases the maximal concentration (Cmax) to 1 μM, and a liposomal formulation of curcumin reaches 10 μM in serum [115, 135]. One trial showed efficacy with 1.6 g of curcumin combined with piperine daily in a phospholipid‐complexed form. After 30 days, participants in the curcumin group had a 5% (p < 0.05) reduction in body weight compared to placebo [114].

2.1.4. Menthol

Menthol, which is isolated from the leaves of the mint plant, is the active component in peppermint oil. Circulating concentrations reach approximately 25 μM in children administered a 540‐mg dose [136]. Historically, menthol has been used to treat digestive disorders because it causes gastric relaxation via effects on enteric nerve receptors [137]. In addition, menthol is an agonist of transient receptor potential melastatin 8 (TRPM8), the primary cold receptor expressed on peripheral sensory nerve terminals in rodents and humans. TRPM8 is also expressed in brown and white adipocytes. Mice administered menthol in an HFD for 7 months resisted HFD‐induced weight gain and had higher core body temperatures and higher insulin sensitivity compared to HFD alone [138]. These effects were not observed in TRPM8(‐/‐) mice. Jiang et al. showed in C57BL/6J mice that dietary menthol stimulates expression of Ucp1, TRPM8, and β3AR in WAT and attenuates HFD‐induced weight gain (Table 1a) [57]. Interestingly, TRPM8 is expressed in human adipocytes. Human adipocyte cultures respond directly to cooling (26°C) or menthol with induction of UCP1, mitochondrial proliferation, glucose uptake, and thermogenesis measured directly with infrared thermography [58].

One clinical trial was conducted to test the acute effects of oral versus topical menthol on human thermogenesis in 20 healthy adults (Table 2). A 7‐h treatment with topical menthol increased metabolic rate by 18% versus a 10% increase by oral menthol [106]. These results were consistent with data showing that oral menthol was eliminated more rapidly than topical menthol [106]. The effects of longer‐term menthol administration have not been tested in clinical trials for weight loss and insulin sensitivity.

2.1.5. Genistein

Genistein is a phytoestrogen present in soybeans, fava beans, coffee, and other plants. The Cmax for genistein in human plasma is approximately 1 μM due to poor intestinal absorption and metabolism in the liver to sulfate and glucuronide conjugates [139, 140]. In mice, genistein is a PPARα and PPARγ ligand, reduces activity of particular tyrosine kinases in adipocytes [141], and inhibits differentiation of adipocytes [142]. Multiple studies have shown that genistein upregulates thermogenesis genes in rodent adipose tissues, but it does not reduce body weight [59, 60, 61, 62, 63]. The effect of genistein on UCP1 expression was studied during differentiation of human SVF preadipocytes from donors with normal weight or overweight. Compared to untreated, 20‐μM genistein stimulated UCP1 expression in preadipocytes from normal weight donors but had no effect on cells from donors who were overweight [63].

2.1.6. ArtC

ArtC is a terpenoid found in the buds and green bark of Baccharis dracunculifolia, and it is concentrated by bees in green beehive propolis that is commonly found in Brazil. Green propolis is rich in polyphenols and antioxidants and is widely used as a supplement in Brazil for its anti‐inflammatory and immune‐boosting qualities [143]. In a human pK study, a single dose of 360 mg of green propolis powder containing 39 mg of ArtC was administered. The study showed that the half‐life is 12 h, and the Cmax in plasma is approximately 1 μM, mostly present as a glucuronide conjugate [144]. It is unknown whether the glucuronide conjugate is bioactive; however, most cell culture and rodent studies have used natural ArtC extracted from bee propolis [64, 145].

Two studies in mice suggest that ArtC is a potent stimulator of nonshivering thermogenesis via effects in WAT without affecting BAT (Table 1a). A daily oral dose of 10 mg/kg of ArtC given to C57BL/6J mice significantly increased inguinal WAT temperature, Ucp1 protein, and mitochondrial creatine kinase 2 (CKMT2) mRNA [64]. In C57BL/6J mice administered 5 or 10 mg/kg of ArtC by gavage for 4 weeks, Ucp1 was induced in WAT and not BAT [46]. In addition, treatment of primary inguinal WAT adipocytes with 10‐μM ArtC during differentiation induced Ucp1 expression approximately 20‐fold over control levels, and these effects required PPARγ activation [46].

Treatment of three human adipocyte cultures with 10‐μM ArtC for 7 days resulted in 18‐fold to 47‐fold higher UCP1 mRNA levels compared to untreated cells [56]. In this study, ArtC stimulated UCP1 expression at a concentration as low as 50 nM. Moreover, combining ArtC (1 μM) with isoproterenol (1 μM), a βAR agonist, synergistically increased UCP1 mRNA threefold over isoproterenol alone in a 4‐h treatment of human adipocytes [56]. ArtC acts in part by binding to CREB, a transcriptional activator of thermogenesis genes stimulated by βARs [145]. ArtC induced additional thermogenesis genes including CKMT1 and PM20D1 in human adipocytes [56]. Considering its efficacy in human cells at nanomolar concentrations, its bioavailability, and its long half‐life, ArtC has great potential for weight loss in human clinical trials.

2.2. Phytocompounds That Induce Ucp1 in Rodent and Not in Human Adipocytes

Ten phytochemicals induce Ucp1 in rodent adipocytes and not in humans. The data for these compounds, epigallocatechin‐3‐gallate (EGCG), fucoxanthine (Fx), quercetin, capsaicin, retinoic acid (RA), apigenin, luteolin, berberine, kaempferol, and myricetin, are summarized in Table 1b. Some compounds were tested in our laboratory in human adipocytes from three donors with obesity using NR extract as a positive control [56]. Of the Table 1b phytocompounds, EGCG, EGCG‐containing green tea extract (GTE), Fx, Fx‐enriched seaweed extract, capsaicin, and RA‐containing mixed carotenoids have been evaluated in human clinical trials (Table 2).

2.2.1. EGCG

Tea is produced from the leaves and buds of the Camellia sinensis plant. The manufacturing process specifically for green tea preserves the phytonutrients, which are predominantly catechin polyphenols. Regularly drinking green tea is associated with beneficial health effects, and the catechin EGCG is the most abundant active compound in GTE [104, 146]. A report in 1999 documented an increase in 24‐h energy expenditure and fat oxidation in humans receiving GTE that was significantly higher than in the caffeine group, and these data ignited interest in GTE as a therapeutic for weight loss [147]. The Cmax for EGCG in human plasma is approximately 1 μM after an 800‐mg dose [148]. In multiple mouse and rat models of HFD‐induced obesity, addition of EGCG to the diet reduces or prevents weight gain [149, 150, 151].

EGCG upregulates thermogenesis genes in primary mouse adipocytes (Table 1b). In adipocytes cultured from mouse inguinal WAT, exposure to 20‐μM EGCG for 8 days increased expression of Ucp1, PPARα, and PGC‐1α [65]. Human adipocytes differentiated from SVF preadipocytes were treated with 1‐μM EGCG for 7 days, and there was no effect on UCP1 levels or TG lipolysis [66]. This study also included a double‐blinded, placebo‐controlled clinical trial, which evaluated the effects of 150 mg of EGCG administered twice daily for 8 weeks in 30 subjects with obesity (Table 2). Compared to the placebo group, there was no effect on body weight, fasting plasma glucose, or insulin [66]. Another 12‐week study in individuals with obesity that tested 150 mg of EGCG twice daily combined with exercise versus exercise alone found no difference between EGCG with exercise and exercise alone, although participants in both groups had reductions in body fat [90].

A randomized, placebo‐controlled trial tested a higher EGCG dose of 300 mg daily for 12 weeks in 83 women with obesity. The results showed no effects on body weight, adiposity, or resting metabolic rate in the fasted state measured by indirect calorimetry (metabolic cart) [92]. A small, 3‐day pilot study was conducted in 10 men with overweight or obesity to investigate the effects on energy expenditure of 300‐mg EGCG, 600‐mg EGCG, 200‐mg caffeine, 300‐mg EGCG/200‐mg caffeine, or placebo. None of the treatments increased fasting or fed energy expenditure compared to placebo [91]. However, elevated fat oxidation was observed with the treatments containing 300‐mg EGCG/200‐mg caffeine or 200‐mg caffeine alone. The largest increase in both fasting (35.4%) and postprandial (49.4%) fat oxidation was achieved with the combination of 300‐mg EGCG/200‐mg caffeine [91]. In summary, clinical trial results indicate that EGCG has no effect on body weight or energy expenditure at doses ranging from 150 to 600 mg daily (Table 2).

2.2.2. GTE

In contrast to purified EGCG, many long‐term clinical trials of whole GTE showed reductions in body weight and body fat (Table 2). We did not include studies of weight maintenance after weight loss [152, 153]. In a 12‐week pilot trial in 34 healthy Japanese men with a mean BMI of 25 kg/m², green tea beverages with approximately 690 or 22 mg (control group) of catechins per day with 75‐mg caffeine were tested for 12 weeks. Subjects were placed on a weight maintenance diet. Compared to the control group, the high dose group showed a reduction of 1.5% (p < 0.05) in body weight and 3.7% in body fat mass [93]. In a large, randomized, double‐blinded clinical trial, the same group in Japan administered green tea with 583 or 96 mg (control group) catechins daily to 240 subjects with abdominal obesity for 12 weeks. The decrease in body weight, body fat mass, waist circumference, and hip circumference was greater in the catechin group than in the control group, with subjects losing 1.7 kg (p < 0.05) of body weight [94].

The popularity of canned and bottled premade tea is growing, and the heat‐sterilization process for packaging produces catechins with a galloyl moiety (CGMs). A 12‐week placebo‐controlled trial was conducted to test the effects of GTEs with 50% of the catechins replaced by CGMs and combined with approximately 35‐mg caffeine [95]. The bottled green tea beverages contained low dose (180 mg) and high dose (280 mg) of catechins and were tested in 126 subjects with obesity who were instructed to maintain their usual diets and physical activity. Compared to placebo, the 280‐mg dose of CGM catechins reduced body weight by 0.5 kg and significantly reduced visceral and subcutaneous fat areas measured by computerized tomography [95].

A 12‐week trial evaluated a high dose of decaffeinated GTE composed of 857‐mg catechins against placebo in 115 women with central obesity. Compared to placebo, weight loss of 1.1 kg was observed in the GTE group with a reduction in waist circumference and total cholesterol [97]. There were no differences in fasting glucose or insulin [97]. In another randomized, placebo‐controlled, 90‐day trial, subjects consumed either two servings of a control drink (30‐mg catechins, 10‐mg caffeine/day), one serving of the control drink and one serving of a high‐catechin drink (458‐mg catechins, 104‐mg caffeine/day), two servings of a high‐catechin drink (468‐mg catechins, 126‐mg caffeine/day), or two servings of the extra high‐catechin drink (886‐mg catechins, 198‐mg caffeine/day) [96]. The extra‐high dose decreased body weight by 1.2 kg (p < 0.05) and reduced % fat mass compared to control in 182 Chinese subjects with overweight [96].

The effect of 60‐day supplementation of 150 mg of GTE twice daily was studied in 28 postmenopausal, sedentary women with obesity. The endpoints were % fat oxidation, % carbohydrate oxidation, and resting energy expenditure measured by indirect calorimetry. There was no change in body weight, although resting energy expenditure, % fat oxidation, and circulating norepinephrine increased [98]. Carbohydrate oxidation, respiratory quotient, insulin, and waist circumference decreased, suggesting that GTE has the potential to counteract some of the long‐term, detrimental metabolic alterations that occur after menopause [98].

Several GTE clinical trials showed no effect on body weight or fat mass at doses higher than 1000 mg/day. A randomized, double‐blind, placebo‐controlled clinical trial on 78 women with obesity was conducted to test the effects of 400 mg of decaffeinated GTE three times a day for 12 weeks. No changes were found in body weight, waist circumference, or circulating adiponectin [99]. A daily dose of 843 mg of decaffeinated GTE was tested for its effects on weight loss in a large trial of 937 postmenopausal women with overweight and obesity [100]. The GTE had 64% EGCG and was ingested in the morning and at night for 12 months. There was no change in BMI, fat mass, visceral fat, or insulin in the GTE group compared to placebo [100]. To evaluate the effects of GTE on weight loss and resting energy expenditure during a 40% energy‐restricted diet, 46 women with overweight were administered 1125 mg of GTE with 255‐mg caffeine or placebo daily for 32 days. Background caffeine intake in all subjects was standardized to 300 mg/day. Reductions in body weight, resting energy expenditure, and fat mass were caused by the low energy diet, but the GTE had no effect compared to the placebo [101]. A randomized, placebo‐controlled trial analyzed the effects of 560‐mg GTE taken daily by 60 men and women with normal weight and overweight for 12 weeks. To determine mechanisms of weight loss, resting energy expenditure and fecal energy content were measured. The results showed that GTE did not cause weight loss or changes in any measured variables [102].

For further insight into the discrepancies between clinical trial results for GTE, the data from two meta‐analyses and a metabolomic analysis have been summarized below. Lin et al. combined all results published through 2019 using the random effects model and found that body weight decreased significantly by 1.78 kg following GTE administration. A dose–response analysis showed that the effect was larger when the GTE dosage was less than 500 mg/day and treatment duration was for 12 weeks or longer [154]. In another meta‐analysis, which pooled data from six trials conducted in Asia on 921 subjects with overweight, the combined results showed that consumption of 540–588 mg of GTE daily for 12 weeks reduced body weight by 1.69 kg and reduced visceral, subcutaneous, and total fat [155]. In a placebo‐controlled, double‐blinded trial, 1200‐mg GTE with 240‐mg caffeine was administered daily to healthy, active males for 7 days, and metabolomic analyses were conducted. The GTE group had elevated levels of lipolysis and fat metabolism and no increase in catecholamine levels, suggesting that adrenergic stimulation was not the primary mechanism [156]. However, this study used a very high dose of GTE, which did not affect long‐term weight loss in clinical trials as noted above. Based on the body of data from GTE clinical trials, the effects on weight loss are modest and the relative contributions of EGCG, caffeine, and other catechins are still undetermined [157, 158].

2.2.3. Fx

Fx is a marine carotenoid that is abundant in edible seaweed and microalgae, and it is converted in the small intestine to the active metabolite fucoxanthinol [159]. A pK study with 18 subjects showed that Fx reaches a Cmax of 44.2 nM 4 h after a single oral dose of 31 mg in a Kombu extract [160]. Circulating fucoxanthinol levels increase over time after continuous intake of Fx. Fucoxanthinol has been measured in human serum at approximately 480 nM 2 weeks after daily oral intake of a 5‐g microalgae capsule containing 30 mg of Fx [161].

Dietary Fx stimulates WAT Ucp1 expression in mice and rats (Table 1b). Two studies in KKAY mice and one in C57BL/6N mice showed that the addition of Fx to the diet increased Ucp1 expression in WAT and reduced adiposity compared to the diet alone [67, 68, 69]. In Wistar rats on an HFD, intragastric Fx for 8 weeks upregulated Ucp1, adiponectin, and PPARƴ in retroperitoneal WAT compared to the HFD group [70].

The effects of fucoxanthinol were examined by Rebello et al. in human adipocyte cultures from individuals with obesity. Treatment for 7 days with 1‐μM fucoxanthinol did not increase UCP1 expression, AMPK activation, basal OCR, or βAR‐stimulated OCR [71]. However, fucoxanthinol stimulated acute lipolysis at concentrations ranging from 0.1 to 1 μM and reduced lipid accumulation after 7 days of treatment [71].

The effect of oral Fx on body weight was investigated in three clinical trials (Table 2). One study randomized 60 subjects with normal weight or overweight into three groups and administered placebo, 1 or 2 mg daily for 8 weeks. Fucoxanthinol levels in serum reached 2.7 nM for the 2‐mg group [103]. The Fx‐treated groups had no change in body weight or fat mass, but blood glucose measured by hemoglobin A1c (HbA1c) decreased in the 2‐mg group and was inversely correlated with serum fucoxanthinol levels [103]. A 12‐week, double‐blinded, placebo‐controlled study measured the effects of daily administration of 12‐mg Fx or placebo in subjects with obesity. There was a modest decrease in body weight of 1.4 kg (p < 0.01), BMI, waist circumference, and TG [162].

A multi‐arm, 16‐week, double‐blinded, placebo‐controlled trial compared energy expenditure stimulated by Fx and Xanthigen, a brown seaweed extract standardized to an equivalent dose of Fx [105]. The subjects were premenopausal women with obesity and normal liver fat or nonalcoholic fatty liver disease (NAFLD). Subjects were administered Fx doses of 1.6, 2.4, 4, and 8 mg, or Xanthigen containing 1.6, 2.4 or 4 mg of Fx three times daily [105]. The minimum effective doses that increased resting energy expenditure compared to placebo at Week 16 were 2.4 mg of Fx and 1.6 mg of Xanthigen; Xanthigen stimulated higher levels of resting energy expenditure compared to Fx at all equivalent doses [105]. These results suggest that there are other active components in Xanthigen, such as omega‐3 fatty acids in brown seaweed, which synergistically enhance the effect of Fx. Importantly, Xanthigen stimulated clinically significant weight loss. The Xanthigen 2.4‐mg dose caused a reduction in body weight of 4.9 kg (p < 0.05 vs. placebo) in the normal liver fat group and 5.5 kg (p < 0.05) in subjects with NAFLD [105]. Changes in body weight were not measured for the Fx‐treated groups. The Xanthigen 2.4‐mg dose had additional beneficial effects including reductions in liver fat, waist circumference, and serum TG (p < 0.05) at Week 16 [105]. The combined clinical study data suggest that Fx alone stimulates resting energy expenditure and causes modest weight loss, and these effects are enhanced by other components present in seaweed extract.

2.2.4. Quercetin

Quercetin and rutin are found in many fruits and vegetables, and quercetin is the main serum metabolite of rutin, reaching a Cmax of approximately 3.5 μM after oral intake of 100 mg [163]. Using a C57BL/6J mouse model of HFD‐induced obesity, two studies showed that the addition of 0.05% or 1% quercetin to the diet upregulated Ucp1 expression in WAT twofold and threefold, respectively (Table 1b) [72, 73]. Neither study showed a reduction in body weight by dietary quercetin [72, 73]. Quercetin did not significantly affect UCP1 levels in human adipocytes from three donors with obesity treated with 10 μM for 7 days [56]. A 12‐week clinical trial conducted in 67 subjects with obesity in Japan tested an extract from quercetin‐enriched onions, containing an equivalent of 60 mg per day. No changes in body weight or total fat were found [164].

2.2.5. Capsaicin

Chili peppers are the most commonly used spice in foods worldwide, and capsaicin is the principal component that causes a hot sensation on the tongue. After oral ingestion of a 5‐g capsule, the peak plasma concentration was approximately 8 nM in humans [165]. The effects of capsaicin on energy expenditure and weight loss have been the focus of a number of studies (reviewed in [166]). Capsaicin activates transient‐receptor potential vanilloid 1 (TRPV1), which is expressed in adipocytes and sensory nerves. In a mouse model of dietary obesity, the addition of 0.01% capsaicin to the HFD diet for 26 weeks prevented weight gain, and these effects were absent in TRPV1(‐/‐) mice [74]. Direct effects on WAT played a key role and included induction of Ucp1, SIRT1, thermogenesis, fat oxidation, and AMPK activation [74]. Takeda et al. showed that in human adipose mesenchymal stem cells, adding 25‐μM capsaicin for 3 weeks during differentiation reduced UCP1 in adipocytes [75].

A 12‐week clinical trial tested 2 or 4 mg per day of capsaicin in 77 participants with overweight or obesity (Table 2). There was no effect on body composition, and 23% of subjects in the high dose group reported GI distress [167]. These studies indicate that capsaicin has limited potential as an obesity therapeutic because of low bioavailability and GI side effects.

2.2.6. Vitamin A/RA

Vitamin A is a metabolite of a subset of carotenoids from fruits and vegetables. Beta‐carotene (BC) and lutein are two of the most abundant pro‐vitamin A carotenoids [76]. Carotenoids are highly lipophilic and accumulate in adipose tissues, resulting in steady‐state plasma levels of approximately 2 μM after consistent dietary intake for 12 months [168]. Studies in animals and humans have demonstrated a strong link between carotenoid supplementation and adipocyte metabolism, inhibition of adipogenesis, and reduced adiposity [169, 170]. RA is a form of Vitamin A that upregulates expression of Ucp1 in brown adipocytes by binding to the nuclear retinoic acid receptor (RAR) and retinoic X receptor (RXR) at the gene promotor [171]. In a mouse model of HFD‐induced obesity, addition of RA to the diet prevented weight gain by activating RAR and PPARβ/δ [172].

The effects of RA on white adipocytes are different in mice and humans (Table 1b). In adipocytes differentiated from mouse embryonic fibroblasts (MEFs), treatment with 1‐μM RA for 24 h induced Ucp1 mRNA and protein [77]. A study that compared the effects of RA in mouse and human adipocytes showed that 1‐μM RA treatment for 24 h induced Ucp1 expression in primary mouse adipocytes by activating RAR [173]. RA did not stimulate UCP1 expression in mature human adipocytes differentiated from primary SVF preadipocytes or from multipotent human adipose‐derived stem cells [173]. However, 14‐day treatment with 10‐μM RA inhibited differentiation of human white preadipocytes to adipocytes [173]. A study conducted in our laboratory using human adipocytes from the subcutaneous WAT of three different donors with obesity showed that treatment with 2‐μM BC for 7 days had no effect on UCP1 expression [174].

Clinical trials investigating the effects of individual provitamin A carotenoids on obesity have not been conducted. However, studies of mixed carotenoid supplementation have all demonstrated beneficial effects on visceral adiposity (Table 2). Ten‐year‐old children with obesity were given a mixed carotenoid supplement for 6 months, and the results showed reductions in BMI, TGs, subcutaneous, and visceral adipose tissue compared to placebo [107]. BC levels correlated directly with elevated serum adiponectin levels [107]. A trial conducted in Japanese men with obesity investigated the effects of test beverages composed of carrot and kale paste on visceral obesity. After 8 weeks of supplementation, BC, lutein, and lycopene were the carotenoids present at the highest levels in serum, and visceral adipose tissue weight was significantly reduced [108]. A large observational study was conducted using data from over 5000 participants in the National Health and Nutrition Examination Survey (NHANES). The analysis showed that serum levels of five carotenoids, among them BC and lutein, were inversely associated with visceral adiposity and circulating TG, HDL, and cholesterol [109].

2.2.7. Apigenin and Luteolin

Luteolin is a hydroxylated metabolite of apigenin, and celery, lettuce, and parsley are foods with high levels of these two flavones [175]. In mice, dietary supplementation with each compound upregulates Ucp1 mRNA in WAT and reduces the detrimental effects of HFD, including weight gain and insulin resistance (Table 1b) [78, 79, 80]. Treatment with 100‐nM luteolin for 24 h induced Ucp1 expression in primary adipocytes from inguinal WAT and epididymal WAT by activation of AMPK [80]. Human adipocytes from three donors with obesity were treated with 10‐μM apigenin or 10‐μM luteolin for 7 days in a study that included 10‐μM NR as a positive control. NR increased UCP1 levels, and there was no effect of apigenin or luteolin in human adipocyte cultures [56].

2.2.8. Berberine

Berberine is a bioactive alkaloid from plants of the Berberis species and several other flowering plants, and it has been used as a traditional Chinese medicine to treat gastrointestinal conditions. A human pK study showed that the Cmax was approximately 1.5 nM using an optimized nanodelivery system to improve bioavailability [176]. Clinical trials in China have shown that berberine has beneficial effects on diabetes outcomes that are similar to metformin [177, 178]. In obese db/db mice that were injected with 5‐mg/kg berberine for 4 weeks, Ucp1 was expressed in adipocytes, and body weight gain was prevented [81]. In this study, berberine induced Ucp1 mRNA in inguinal WAT via AMPK activation, but there was no upregulation in other WAT tissues. Thermal imaging showed a robust effect on BAT activation that likely contributed to most of the energy expenditure [81]. Three human adipocyte cultures were treated with 10‐μM berberine for 7 days, and no increase in UCP1 expression was observed [56].

2.2.9. Kaempferol

Kaempferol is a flavonoid found in traditional medicinal plants like Ginkgo biloba and in tea, fruits, and vegetables. In C57BL/6J mice fed an HFD, 25‐, 50‐, or 100‐mg/kg kaempferol administered by gavage with HFD prevented weight gain and adiposity, and the 50‐mg/kg dose had the strongest effect [82]. This effect was due to elevated Ucp1 expression and energy expenditure in WAT, and there was no effect on BAT [82]. Kaempferol also inhibited adipogenesis via suppression of cyclin‐dependent kinase‐6 activity [82]. In three human adipocyte cultures treated with 10‐μM kaempferol for 7 days, there was no increase in UCP1 mRNA [56]. A clinical trial showed that daily supplementation with 50 mg of kaempferol for 4 weeks is safe in humans and causes no changes in blood markers [179]. Additional clinical research will be required to determine its bioavailability and potential to treat metabolic diseases.

2.2.10. Myricetin

Myricetin is a polyphenol present in many vegetables, fruits, tea, and cranberries [180]. In db/db mice, treatment with a high dose of 400 mg/kg of myricetin by gavage for 14 weeks upregulated Ucp1 expression in BAT and in WAT, increased nonshivering thermogenesis, and reduced blood glucose and body weight [83]. In a diet‐induced obesity model of C57BL/6J mice fed an HFD for 8 weeks, treatment with 10‐mg/kg myricetin for 2 weeks resulted in many beneficial effects including a reduction in body weight, glucose, and serum TG [84]. However, Ucp1 expression in WAT was unchanged [84]. Treatment with 10‐μM myricetin for 7 days did not induce UCP1 in human adipocyte cultures from three donors with obesity [56]. There is little clinical data available for myricetin bioavailability or effects on weight loss.

3. Discussion

Obesity is a chronic disease that elevates the risk for diabetes, cardiovascular disease, fatty liver diseases, cancer, and other diseases. Incretin receptor agonists are a new class of obesity drugs that promote weight loss of 20% or higher by suppressing appetite [181]. However, these drugs have adverse side effects, and substantial loss of lean mass accompanying weight loss is a concern [4, 182]. Rather than targeting brain neural circuitry to reduce hunger and food intake, an alternative strategy is to reduce fat stores directly by reprogramming adipocytes to utilize TGs for thermogenic energy expenditure. UCP1 is a gene marker specific for browning of adipocytes and activation of mitochondrial thermogenesis [183]. After a search of peer‐reviewed literature, we found publications documenting 16 phytonutrients that upregulate Ucp1 expression in rodent WAT and reduce body weight. All of these natural compounds have been tested in human adipocytes, and many were analyzed in our laboratory in fat cells from three or more adults with obesity. A key finding is that out of the 16 phytonutrients reviewed, only NR, curcumin, menthol, and ArtC stimulate UCP1 expression in mature human adipocytes treated with concentrations that can be physiologically reached in human plasma after ingestion. These data suggest that human adipocytes are less responsive to agents that stimulate browning in mice and may be a more discriminating model for preclinical testing of weight loss supplements that target WAT thermogenesis [184].

The mechanisms for induction of UCP1 in human adipocytes vary. Menthol is an activator of the TRPM8 cold receptor and a weak inducer of UCP1 at its Cmax of 25 μM [58, 185]. The mechanism for curcumin is unknown. The most potent activators of human UCP1 expression, NR and ArtC, bypass receptor signaling and bind transcription factors in the nucleus at promotor elements of metabolism genes. NR is a ligand of PPARγ and PPARα and ArtC binds CREB [44, 145]. An early analysis of the human UCP1 promoter identified a strong enhancer containing a PPAR‐responsive element, a retinoic acid‐responsive element, and a cAMP‐responsive element that interact synergistically [186]. NR and BC, a PPAR ligand and an RA precursor, synergistically elevate levels of UCP1 and other genes for thermogenesis and insulin sensitivity in human adipocytes [31]. Addition of ArtC to NR and BC further amplifies UCP1 levels in human adipocytes [56]. Considering that NR alone stimulates weight loss and that these transcriptional mechanisms also upregulate fat oxidation in liver [129, 145], these data suggest that this combination of phytocompounds has the potential to stimulate consequential weight loss.

Of the phytocompounds in Table 2 that have been evaluated in clinical trials, only curcumin and NR stimulated weight loss and insulin sensitivity in multiple studies. Maximum weight loss was 3.9 kg (p < 0.05) for curcumin in a 9‐month trial at a dose of 1.5 g per day and 2.5 kg (p < 0.002) for NR in a 4‐week trial at a low dose of 200 mg/day [113, 116]. Menthol increased energy expenditure in multiple trials in which weight loss was not measured. RSV stimulated weight loss in a single trial at the highest dose tested, but the effect was not repeatable with the same dose or other doses in many other trials [88]. Fx caused mild weight loss of 1.4 kg (p < 0.01) in individuals with obesity consuming 12 mg/day for 12 weeks [162]. However, a seaweed extract enriched in Fx administered at 12 mg/day for 16 weeks reduced body weight by 5.5 kg (p < 0.05) and increased energy expenditure. Although the Fx active metabolite fucoxanthinol did not induce UCP1 or energy expenditure in human adipocytes [71], multiple studies have shown that Fx has beneficial effects on liver fat metabolism. The liver is a metabolically active organ and key contributor to basal metabolic rate [187], and Fx induced fat oxidation and inhibited lipogenesis in three human liver cell lines used as models for fatty liver disease [188, 189, 190]. Two additional clinical trials showed that Fx supplementation reduced hepatic steatosis, fibrosis, BMI, and insulin resistance in subjects with NAFLD [189, 190]. These data suggest that Fx has therapeutic value for individuals with fatty liver disease. Capsaicin, EGCG, and RA did not induce UCP1 in human adipocytes and did not stimulate clinical weight loss. However, GTE enriched in EGCG and mixed carotenoids containing RA caused mild reductions in body weight and fat mass. Except for Fx, which acts on liver, the data in this review show that individual phytonutrients that did not induce UCP1 mRNA in human adipocytes did not stimulate weight loss in clinical trials.

An important characteristic of phytonutrients is bioavailability. Ingested phytocompounds are absorbed at different regions in the intestine at varying levels, and most are converted to inactive metabolites to some extent by intestinal cells, gut microbiota, and the liver [191]. RSV is so rapidly converted to inactive metabolites that it has little efficacy in clinical studies (Table 2). Curcumin has low bioavailability; however, the addition of piperine or administering a high dose of 1.5 g/day consistently stimulates clinical weight loss. Human pK studies that determine serum levels and kinetics of the active metabolites are essential [191]. Based on human pK studies, it is rare for circulating concentrations of phytonutrients to reach above 10 μM [148, 163, 192]. Preclinical analyses of activity in human cell cultures should be conducted with the active metabolites at achievable circulating concentrations for meaningful results. However, a limitation of cell culture studies is that they do not always reflect physiological conditions in which metabolites, hormones, and other factors may alter efficacy in vivo. Many phytonutrients have been designated by the FDA as generally recognized as safe, GRAS, if they have a history of consumption by humans in the United States [193]. GRAS phytonutrients do not require FDA approval and would be less costly to develop than compounds that are not GRAS or need nanodelivery systems, requiring FDA approval and safety clinical trials.

4. Conclusions

UCP1 is a marker of thermogenic capacity in adipocytes. A literature search identified 16 phytocompounds that stimulate Ucp1 expression in primary rodent WAT or adipocytes. NR, menthol, curcumin, and ArtC induce UCP1 in mature human adipocytes treated with achievable plasma concentrations measured in human pK trials. The phytocompound data summarized in this review suggest that robust induction of UCP1 and thermogenesis genes in human adipocytes, effects on liver lipid metabolism, and high bioavailability are key characteristics for weight loss in clinical trials. In general, studies that demonstrated weight loss also demonstrated improvements in other metabolic outcomes. NR and curcumin stimulated weight loss as single compounds. Enriched extracts of Fx (seaweed) and EGCG (green tea) stimulated weight loss; however, the active components Fx and EGCG had little efficacy in clinical trials. A potential strategy to achieve greater weight loss is to combine bioavailable phytonutrients with synergistic mechanisms. For example, treatment with combinations of natural ligands for the transcriptional activators PPARα/γ, RXR, and CREB amplifies expression of key thermogenesis genes in adipocytes [31, 56]. The data reviewed herein show that certain phytonutrients and extracts stimulate energy expenditure with weight loss and support further development.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.