Table 2.

Overview of pharmacotherapy for obesity.

Targeted Pathway	Pathophysiologic Basis	Drug	Side Effects/Observations
Polypharmacy	Combined ampheta-mines, diuretics, thyroid hormones	Agent type: energy intake and expenditure Rainbow pills approved in 1941–1968 (FDA) [273]	Insomnia, palpitations, anxiety, increase in heart rate and blood pressure, death [276]
Sympathicomimetic	Release of norepi-nephrine, dopamine, and serotonin at the nerve terminals Inhibition of the reuptake of monoamines, increasing their synaptic levels [277]	Agent type: energy intake and expenditure Methamphetamine approved in 1947–1979 (FDA)	High risk for abusiveness and addiction [276]
Sympathicomimetic	Amphetamine con geners Direct α-adrenergic agonism Indirect stimulation of norepinephrine release, similar to ephedrine’s effect [278]	Agent type: energy intake and expenditure Phenylpropanolamine approved in 1976–2000 (FDA) [273]	Hemorrhagic stroke [276]
Sympathicomimetic	Phenylalkylamine sympathomimetic, similar to amphetamine [279]	Agent type: energy intake and expenditure Phenmetrazine (active compound) 1956–present (FDA) Phendimetrazine * (prodrug) 1959–present (FDA) for short term use	Nausea, diarrhea, dry mouth [276,280]
Sympathicomimetic	Amphetamine congeners [273]	Agent type: energy intake and expenditure Diethylpropion/am-fepramone * was approved in 1959 (FDA) for short-term use, withdrawn in 2022 (EMA) [281]	Pulmonary hypertension, psychiatric disorders [276,282,283]
Sympathicomimetic	Amphetamine congeners [273]	Agent type: energy intake and expenditure Benzphetamine * approved in 1960 (FDA) for short term use	Agitation, anxiety, confusion, dizziness, fast heartbeat
Sympathicomimetic	α1-adrenergic agonist Modulates neuronal activity in the nucleus accumbens shell, acting on dopamine D1 and D2 receptors [284]	Cathine (D-norpseudoephedrine) approved in 1975 (EMA) for short- term use, ≤12 weeks [276]	Tachycardia, increase in blood pressure, restlessness, sleep disorder, and depression [276,285]
Sympathicomimetic	A norepinephrine and serotonin reuptake inhibitor	Agent type: energy intake Sibutramine 1997–2010 (FDA, EMA)	Headache, insomnia, dry mouth, constipation, non- fatal myocardial infarction, and stroke (in individuals with pre- existing cardio-vascular diseases) [276,286]
Sympathicomimetic	Amphetamine congeners [273,287]	Agent type: energy intake and expenditure Phentermine * 1959–present (FDA) for short-term use	Dry mouth, insomnia, palpitations, tachycardia, hypertension, anxiety, dizziness, and constipation [274,276,286]
Sympathomimetic/anticonvulsant	Phentermine in creases mainly norepinephrine in the hypothalamus [275] Topiramate blocks voltage dependent sodium channels, glutamate receptors, and carbonic anhydrase, and augments GABA activity, promotes taste aversion, decreases caloric intake, and stimulates lipolysis [287]	Agent type: energy intake Phentermine/topiramate * approved in 2012 (FDA) for adults with BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with at least one weight-related comorbidity but refused twice by EMA [288]	Elevation in heart rate, mood and sleep disorders, cognitive impairment, depression, suicidal ideation, metabolic acidosis, paresthesia, dry mouth An increased risk of cleft lip/palate in infants with exposure during the first trimester of pregnancy [274,289,290]
Sympathomimetic	ß3-adrenergic recep-tor agonist, which primarily targets the brown adipose tissue [291]	Agent type: energy expenditure Mirabegron approved in 2012 (FDA) for treating incontinence, phase II for obesity [292]	Hypertension (most com monly), nasopharyngitis, and urinary tract infection [276,293,294,295]
Combinations Targeting the Neurotransmitters and Neuropeptides	Bupropion is a reuptake inhibitor of dopamine and norepinephrine that promotes activation of the central melanocortin pathways Naltrexone is a com petitive MOR and DOR antagonist that exhibits synergic effects with bupropion (increases the release of anorexigenic melanocortins such as α-MSH and β-MSH Naltrexone diminishes the feedback inhibition caused by beta-endorphins which are known to stimulate food intake) [287,288,296]	Agent type: energy intake Bupropion/Naltrexone * 2014 (FDA), 2015 (EMA) [288]–indicated for long term use The combination of bu-propion with zonisamide was also investigated (phase II) [297]	Nausea, constipation, head ache, vomiting, dizziness, insomnia, dry mouth, seizures, and palpitations [273,276,287,289] Caution in patients treated with antidepressants and some antipsychotics [274]
Combinations targeting the Neurotransmitters	Multimode inhibitor of norepinephrine, serotonin, and dopamine reuptake/beta1 blocker	Agent type: energy intake Tesofensine/metoprolol (phase IIb–for hypothalamic obesity) [290]	Increased heart rate for tesofensine [298,299]
Targeting Dopamine pathway	Dopamine reuptake in hibitor Increases brain synap-tic dopamine action on the nucleus accumbens, and striatum [300]	Agent type: energy intake and expenditure Methylphenidate (phase III) [289,301] (approved by FDA for the treatment of attention-deficit/hyperactivity disorder or narcolepsy)	Irritability and insomnia [302]
Targeting Serotonin pathway	Stimulates the release of serotonin and inhibits its reuptake in the synaptic cleft	Agent type: energy intake Fenfluramine 1973–1997 (FDA) Fenfluramine associated with phentermine (never approved by FDA) Dexfenfluramine 1996–1997 (FDA)	Valvular regurgitation in sufficiency (direct stimulation of 5- H T2B receptors on the interstitial cells of the mitral and aortic valves), primary pulmonary hypertension, and cardiac fibrosis [273,303,304]
Targeting Serotonin pathway	Suppression of NPY/AgRP neurons Stimulatation of POMC/CART neurons Activation of melanocortin 4 receptor pathway [305]	Agent type: energy intake 5-HT2C receptor agonist Lorcaserin 2012–2020 (FDA), never approved by the EMA [287,306,307].	Increased incidence of certain cancers
Cannabinoids pathway	Decreases appetite, enhances thermogenesis, and diminish lipogenesis Cannabidiol activates the endocannabinoid system, 5HT-1A receptors, PPAR- γ and inhibits anandamide reuptake [308]	Agent type: energy intake CB1 R inverse agonist Rimonabant never approved by FDA, 2006–2008 EMA [290] Taranabant (discontinued) AM251 (preclinical) [309] Peripheral CB1 R inverse agonist AM6545 [275] JD5037 (phase I for Nonalcoholic steatohepatitis) [310,311] FB-024 for kidney disease [273] CB2 R antagonist JWH-015 (preclinical) Cannabidiol solution RAD011 (phase III–for Prader-Willi syndrome) [308,312]	Hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence (cannabidiol) [313] Warnings regarding drug-drug interactions [313]
Entero-endocrine pathway Incretin mimetics Glucagon-like peptide-1 (GLP-1)	Decreases appetite through direct activation of POMC/CART neurons [273,276] and suppression of AgRP/NPY neurons through GABA-dependent signaling [273,276]	Agent type: energy intake GLP-1 agonists/analogs Human GLP-1 backbone: Liraglutide * approved in 2014 (FDA), 2015 (EMA) for the treatment of adult obesity; approved in 2020 (FDA), 2021 (EMA) for the treatment of obesity in adolescents aged 12–17 years [314] Semaglutide * approved in 2014 (FDA), 2015 (EMA) for adults with BMI ≥ 30 kg/m2 or BMI ≥27 kg/m2 with at least one weight-related comorbidity), approved in 2021 (FDA), 2022 (EMA) for teens ages 12 and up who have a BMI at or above the 95th percentile for their age and sex [315,316]. Dulaglutide (registered for the treatment of T2D) but exhibiting weight reducing effects [294,317] Exendin-4 backbone: Exenatide (registered for the treatment of T2D) but exhibiting weight reducing effects [294] Lixisenatide Pipeline drugs: Efpeglenatide (phase III) Rybelsus (phase III) Danuglipron (PF-06882961) (phase II) GLPR- NPA (phase I) PF-07081532 (phase I) [276,318] Noiiglutide (SHR20004) (phase II) [319] LY3502970 (phase II) [320] XW003 (phase II) [289,321] XW004 (phase I) [273]	Increased heart rate, hypo glycemia, constipation, diarrhea, nausea, vomiting, headache, reversible increases in amylase/lipase activity (liraglutide) [287,289,322] Nausea, vomiting, diarrhea, abdominal pain, constipation, and headache (semaglutide) [289] Warnings about personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2, pregnancy [289] Semaglutide induces greater weight loss compared to currently FDA-approved drugs (of up to 15–30% of baseline body weight as compared to 5–10%), which opens a new era in the pharmacotherapy of obesity [273,323]
Entero-endocrine pathway–Incretin mimetics	Increases insulin production and decreases hepatic glucose overproduction	Agent type: energy intake DPP-4 inhibitor Yogliptin (phase III for T2D) [273]	Potentially reduced risk for acute pancreatitis described for drugs found already in use for the treatment of T2D [324]
Entero-endocrine pathway–Incretin mimetics Glucose- dependent insulinotropic polypeptide (GIP) pathway–also known as gastric inhibitory polypeptide [325]	Postprandial potentiation of insulin secretion Activation and blocking of the GIPR receptor have both been shown to decrease body weight GIP regulates energy metabolism via CNS GIPR signaling [276,325]	Agent type: energy intake GIPR agonists GIPR agonist long acting (phase I for T2D) ZP 6590 (preclinical for obesity) Antagonistic GIPR antibodies [325,326,327] GIP Receptor Antagonist SKL-14959 [328]	GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis [329,330]
Pancreatic hormones pathway Glucagon	Increases blood glu-cose levels [331] Stimulates lipolysis and thermogenesis in brown adipose tissue Satiety via mediated via the liver-vagus-hypothalamus axis [276] The thermogenic effect is determined by the feeding status [276,332]	Agent type: energy intake Glucagon Analog HM15136 (phase I) [276] NN9030/NNC9204–0530 [273] Non-peptide glucagon receptor antagonist Bay 27–9955, LY2409021–discontinued [333]	Not known to date
Entero-endocrine pathway (twincretins) GIP/GLP-1	Mimics the actions of native GIP at the GIP Diminishes GLP-1 re-ceptor internalization Acts on arcuate nu-cleus and other hypothalamic regions, parietal cortex, insula, putamen, orbitofrontal cortex, adipose tissue, and gastrointestinal tract [289,334]	Agent type: energy intake GIP/GLP-1 dual agonist Tirzepatide * 2022 (FDA) [294,335,336] GIP/GLP peptide I (phase I–for T2D) GIP/GLP peptide II (phase I–for T2D) SCO-094 (phase I) [331] NN9709, formerly MAR709 and RG7697 (phase II–stopped) [276,331,337] CT-868 (phase II) AMG133 (phase I) [273] GMA106 (phase I) [338] CT-388 (phase I) [289,339]	Gastrointestinal side effects: nausea, diarrhea, vomiting, mild hypoglycemia [289,336,340] Caution for people with a personal or family history of medullary thyroid carcinoma. Patients with a history of multiple endocrine neoplasia type 2 (MEN 2) [294]
Pancreatic-entero-endocrine pathway GLP1/glucagon	Mimics the effects of GLP-1 and glucagon receptor activation [289]	Agent type: energy intake GLP1/glucagon dual agonists Cotadutide (MEDI0382) (phase IIb) BI 456,906 (phase II) Efinopegdutide (JNJ-64565111/HM12525A/MK6024 (phase IIa) Mazdutide (IBI362/LY3305677) (phase III) [289,331,341,342] JNJ-54728518 (phase I) [331] NN9277/NNC9204–1177 (phase I–stopped) CT-868 (phase 2) DD01 (phase 1) ZP2929 (phase I) TT-401 (phase II for D2T) Oxyntomodulin (OXM) analogs [276,343] G3215 (phase I) IBI362/LY3305677 (phase II) MOD-6031 (phase I) OPK-88003/LY294487 [273] (phase II) Oxytocin (phase II–for hypothalamic obesity) [289]	Nausea and vomiting (cotadutide and efinopegdutide) [333,344] Caution for patients with cardiovascular conditions (oxytocin) [345]
Pancreatic-entero-endocrine pathway GLP1/GIP/glucagon	Mimics the effects of GLP1, GIP, and glucagon activation Acts on the parietal cortex, insula, putamen, orbitofrontal cortex, arcuate nucleus and other hypothalamic regions, gastrointestinal tract, adipose tissue, liver	Agent type: energy intake GIP/GLP1/glucagon tri-agonists HM15211 (phase II for NASH) Peptide 20 (MAR423) (phase I) [331] Retatrutide (LY3437943) (phase II) [289,331,346] SAR441255 (phase I -stopped) [273] NN9423/NNC9204–1706 (phase I) [273]	Not known to date
Entero-endocrino pathway Cholescystokinin (CCK)	Short-term regulator of food intake reduction Transmits the satiety signal via the vagus to the brainstem, from which the satiety signal is projected to the hypothalamus [276]	Agent type: energy intake Cholecystokinin-1 receptor agonist GI181771X [347,348] (phase II–stopped) NN9056 (preclinical) [349,350] Positive allosteric modulators of CCK type 1 receptor–under investigation (preclinical) [351]	Delayed gastric emptying of solids [350], did not reduce body weight (GI181771X) [352] Induce acute pancreatitis and pancreas neoplasia in rodents, but not in primates [349]
Entero-endocrine pathway Peptide tyrosine tyrosine (PYY)	Co-secreted from the intestinal L cells as PYY1-36, together with GLP1 The bioactive form is PYY3-36 produced by cleavage of 2 amino-acid residues from PYY1-36 by DPP-IV PYY3–36 is a high-affinity agonist at the NPY receptor type 2 (Y2R). Decreases activity of NPY neurons and activate POMC neurons [276,353]	Agent type: energy intake PYY3–36 analogues NN9747 (PYY 1562 analogue) PYY analogue in combination with metreleptinb (leptin analogue) or amylin analog [350] NN9748, NNC0165-1875 (phase I) NNC0165-1875 in combination with semaglutide (phase II) [276] Combination of PYY, GLP-1, and oxyntomodulin administered as subcutaneous infusion [354]	Nausea was described in compounds from the same class [355]
Entero-endocrine pathway Neuropeptide Y	Orexigenic neuro peptide belonging to the neuropeptide Y family Is found at all levels of the gut–brain, and brain–gut axis [353] Promotes energy storage in white adipose tissue Inhibits brown adipose tissue activation [356]	Agent type: energy intake Type 5 neuropeptide Y receptor antagonist MK-0557 [278] (phase II) [275,357] Velneperit (phase IIb) [275,294,358]	Good tolerance [275]
Melanocortin system	Activation of POMC/CART neurons leads to the secretion of α- MSH, which activates MC4R to inhibit food intake Activation of NPY/AgRP neurons leads to the secretion of AgRP, which stimulates food intake through blocking of the melanocortin 4 receptor (MC4R) [276]	Agent type: energy intake Structurally related MC4R agonist Setmelanotide * approved in 2020 (FDA), 2021 (EMA)–treatment of obesity in patients aged 6 or older with proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency, confirmed by genetic testing); approved in 2022 (FDA, EMA) for Bardet-Biedl syndrome) [276,287,289,359,360] LY2112688, MC4- NN-0453, MK-0493, AZD2820 (stopped in clinical phases due to lack of efficacy) [361]	Injection site reactions, hyperpigmentation, nausea, spontaneous penile erections in males, depression, and suicidal ideation (setmelanotide) [362]
Entero-endocrine pathway Ghrelin pathway	Short-term regulators, secreted in anticipation of food intake) Ghrelin is one of the most important orexigenic neuropeptides and represents the ligand of the growth hormone secretagogue receptor (GHS-R1a) In fat tissue, ghrelin increases fat storage [363] Uses vagal signaling, in order to stimulate food intake [363] Activation of NPY/AgRP neurons in the hypothalamus [276]	Agent type: energy intake Ghrelin neutralization: CYT009- GhrQb vaccine (phase I, lack of efficacy) NOX-B11-2 and NOX-B11-3 spiegelmers, antisense polyethylene glycol-modified L-oligonucleotides capable of specifically binding a target molecule (preclinical) [276,364] GHS-R1a Antagonists [D-Lys-3] GHRP-6, YIL-781, JMV2866, JMV2844, TZP-301 [364] GHS-R1a Inverse Agonists [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P Bitter taste receptor (T2R) antagonists ARD-101 (phase II) [365] Ghrelin-O-acyltransferase (GOAT) inhibitor: GLWL 01 (phase II for Prader-Willi) [19,366] GHSR antagonists and inverse agonists: Liver-enriched antimicrobial peptide 2 (LEAP2), the des-acyl form of ghrelin (DAG) (phase I) [276,367]	AZP-531–discontinued due to hyperphagia in patients with Prader–Willi syndrome [276]
Leptin pathway	Long-term regulators of food intake Communicates signals to the cerebral cortex conforming to the amount of lipid stored in the organism. Inhibits orexigenic pathways and activate anorexigenic pathways targeted to suppress appetite Activation of POMC neurons and inhibition of AgRP neurons in the ARC [276,368] Site of action: adipose tissue, liver, hypothalamus [289]	Agent type: energy intake Recombinant analog of the human hormone leptin Metreleptin * approved in 2014 (FDA), 2018 (EMA) for individuals with congenital leptin deficiency MetHuLeptin [368] Pegylated recombinant leptin PEG-OB [368,369] Leptin sensitizers: ERX1000 (phase I) [273,289] Withaferin A (bioactive A compound derived from traditional Chinese medicinal herbs of the Celastraceae family) (phase I) Celastrol (C28 steroidal lactone derived from Ashwagandha) (preclinical) [370,371] Leptin/amylin discontinued [276]	Low effect in polygenetic obesity Antibodies appearance (metreleptin) [372]
Amylin pathway	Decreases homeostatic food intake Co-secreted with insulin from the pancreatic β- cells Activates calcitonin gene-related CGRP signaling through the AP area postrema. Signaling through the mesolimbic dopamine system in the ventral tegmental area and the nucleus accumbens (NAcc) [276,294]	Agent type: energy intake Amylin agonists Pramlintide registered for T2D treatment [373] Cagrilintide (phase III) in combination with semaglutide [276,289,294] AC164204, AC164209 (davalintide in combination with GLP-1R analogue) (preclinical) [275] NNC0174-0833 (phase II) [275,289] ZP8396 (phase I) [273,276]	Administered in different combinations [294]
Amylin and calcitonin pathway	Calcitonin of mammalian origin promotes insulin sensitivity Salmon calcitonin decreases gastric emptying, enhances energy expenditure, and promotes satiety [374]	Agent type: energy intake Dual- acting amylin and calcitonin receptor agonists (DACRAs) KBP-089 (phase II–T2D) Davalintide (AC2307) –discontinued KBP-088 [375] KBP-042 (phase II–T2D) [276]	Weight loss in animal models
Sodium-glucose co-transporters (SGLT) pathway	Blocks reabsorption of filtered glucose in the kidney, increasing urinary glucose excretion and reducing blood glucose levels Site of action: kidney, adipose tissue	Agent type: energy expenditure SGLT2 inhibitors registered for the treatment of T2D but exhibiting weight loss effects: canagliflozin, dapagliflozin, empagliflozin, bexagliflozin [19,294] Dual sodium-glucose transporter (SGLT)-1 and -2 inhibitor licogliflozin (LIK066) [376,377], sotagliflozin for T2D [378]	Gastrointestinal dose-related side effects: diarrhea, flatulence, urinary infections, ketoacidosis (SGLT2) SGLT2 and phentermine co administration resulted in significant body weight reduction from baseline compared to monotherapy [275]
Modulation of PPAR gamma pathway	Regulation of adipocyte differentiation and lipid storage	Agent type: energy storage AMG 133 (phase I) [379] MBL949 [289,380]	Not known to date
Phosphodiesterase-4 (PDE4) pathway	Influences the expression of the adipogenesis genes such as SREBP1C, FABP4, Glut4, and regulators as PPAR-γ via activation of the AMPK-mediated pathway [381]	Agent type: energy storage and expenditure PDE4/5 inhibitor Roflumilast (phase III) [382] Tadalafil (phase II)	Mainly gastro-intestinal [383]
Sirtuin 1 (Sirt1) pathway	Modulates energy metabolism Influences transcription of factors via the PPAR pathway [384]	Agent type: energy storage NS-0200 (combination of leucine, metformin, and sildenafil) (phase II) [385]	Not serious
Targeting mitochondrial uncouplers pathway	Increase energy expenditure, increase mitochondrial inefficiency, and renders ATP less efficient At therapeutic doses can protect cells against death but in high concentrations are cytotoxic due to a drop in ATP concentration and lysosomal membrane permeabilization [276]	Agent type: energy expenditure 2,4–dinitrophenol (DNP) 1933–1938 (FDA) BAM15 (preclinical) [276]	Side effects: hyperthermia, tachycardia, diaphoresis, fever, tachypnoea, and death [273] Benefits: improves insulin sensitivity in multiple tissues
Fibroblast growth factor 21 (FGF21) pathway	Secreted mainly from the liver in fasting conditions Activation of brown fat thermogenesis and augmented secretion of adiponectin [276,294,386]	Agent type: energy expenditure FGF21 analog: LY2405319 (modified human FGF21 expressed in yeast) PF05231023 (two FGF21 joint with an IgG backbone) [387] Pegbelfermin (BMS986036) (peglylated human FGF21) Efruxifermin (AKR-001 Fc-FGF21 engineered fusion protein) (phase I–for D2T) [388] AMG876 [246,299,386,387,389] FGF21-receptor agonists: C3201–HAS MimAb1 39F7 mAb FGF21 mimetics: BFKB8488A NGM313 [389,390] FGF21/FGFR1c/β-Klotho signaling LLF580 (phase I) MK-3655/NGM313 (phase I) NN9499/NNC0194-0499 (phase I)	Raised heart rate and blood pressure (PF-05231023) Moderate bone resorption
Farnesoid X receptor (FXR) (also known as bile acid receptor) pathway	Effects also mediated by FGF 19 and 21 CYP7A1 inhibition stimulates cholesterol excretion into bile and intestinal lumen [391]	Agent type: energy expenditure FXR agonist obeticholic acid derivatives: EDP-305, INT-767, INT-787 Non-steroidal compounds: MET409, tropifexor, cilofexorlization, vonafexor, TERN-101, ASC42, EDP-297, HPG1860, and HPG7233 (phases I and II for NASH) [391]	Pruritogenic potency of obeticholic acid derivatives [392]
Fibroblast growth factor receptor 4 (FGFR4) pathway	Decreases the body’s ability to store fat while simultaneously increasing fat burning and energy expenditure [393,394]	Agent type: energy expenditure FGFR4 inhibitor IONIS-FGFR4Rx an anti sense drug that diminishes the production of FGFR4 in the liver and fat tissues (phase II) [395]	Expected not to produce any CNS side effects are due to the fact that it is not distributed to the brain [396].
Macrophage inhibitory cytokine 1 (MIC-1; also known as growth differentiation factor GDF15) pathway	Belongs to TGF-β superfamily Activation of the GDNF family receptor α- like (GFRAL) [397] GDF15-GFRAL-mediated regulation of food intake is by a central mechanism [397] Possible induction of nausea and engagement of emetic neurocircuitries [276]	GDF15 agonist/analog LA- GFD15 (phase I) LY–3,463,251 (phase I) JNJ-9090/CIN-109 (phase I) [276]	Mild gastrointestinal side effects [398]
Cholinergic pathway	Releases GLP-1 and PYY [399]	Agent type: energy intake α7-nAChR agonist GTS-21/DMXB-A (phase I) [273]	Not known to date
Activin type II receptor (ActRII) pathway	Prevents the actions of natural ligands that negatively regulate skeletal muscle growth Activates functional brown adipogenesis and thermogenesis through increasing mitochondrial function [275]	Agent type: energy expenditure A fully humanized monoclonal antibody against activin type 2 receptors Bimagrumab (BYM338) (phase II) [400]	Mild diarrhea and muscle spasms [400]
Glabridin (prenylated isoflavan from the roots of Glycyrrhiza glabra) [401]	Acts on signaling pathways, including NF-κB, MAPK, Wnt/β-catenin, ERα/SRC-1, PI3K/AKT, and AMPK Site of action: muscles, Liver	Agent type: energy expenditure Glabridin analogue HSG4112 (phase I) [273,402]	Not known to date
Labisia pumila extract	Upregulation of PPARgamma pathway [403]	Agent type: energy storage SKF7 (phase II) was accepted as a food supplement in 2015 in the EU [404,405]	Not known to date
Probiotics	Anaerobic, Gram The negative and mucin-degrading bacterium of the phylum Verrucomicrobia [406]	Agent type: energy absorption Akkermansia muciniphila WST01 strain (phase II) [407]	Damaged the intestinal barrier Changes the bile acid metabolic profile when administered after antibiotics [408]
Melatonin pathway	Influences circadian rhythm, gut microbiota, sleep patterns, α7nAChR, and the opioidergic system [409,410] Protects against obesity-induced renal side-effects by inhibiting endoplasmic reticulum stress/apoptosis pathway [411]	Agent type: energy expenditure [412] Melatonin receptor agonists for the treatment of circadian rhythm sleep-wake disorders Prolonged-release melatonin (approved by EMA) Agomelatine (approved by EMA) Tasimelteon (approved by FDA and EMA) Ramelteon (approved by FDA) [410,413]	Safe in the short-term treatment and without abuse potential (tasimelteon) [414] Low-dose melatonin supplementation was not associated with low testosterone levels [415]
Thyroid hormones pathway	Upregulates free fatty acid uptake and oxidation stimulating lipolysis Enhances mitochondrial biogenesis and respiration, leading to increased energy expenditure. Activation of bile acid synthesis [391]	Agent type: energy expenditure THR-β agonist ASC41 (phase II for NASH) [416]	Reduced cardiac effects due to the fact that the TRβ receptor subtype is mainly expressed in the liver compared with TRα, which is mainly expressed in the heart [417]
Methionine aminopeptidase (MetAP) 2 pathway [299]	Reduces fat biosynthesis, and increases fat oxidation and lipolysis [288]	Agent type: energy expenditure MetAP2 inhibitor Beloranib (ZGN-440) (phase III for Prader-Willi Syndrome) [418]	Injection site bruising, venous thrombotic events [419]
Vitamin E pathway	Regulates pathways of lipid metabolism and fatty acid biosynthesis Reduces the expression of transcription factors regulating adipogenesis and increasing apoptosis of adipocytes [420]	Tocotrienols (phase I) [289,421]	Not known to date
Diacylglycerol acyltransferase 1 (DGAT) pathway	DGAT1 plays a role in very VLDL synthesis DGAT2 plays a role in steatosis	Agent type: energy storage DGAT1 inhibitor AZD7687 [422] DGAT2 inhibitor Ervogastat/PF-06865571 [273]	Nausea, vomiting and diarrhoea (DGAT1 inhibitor) [423] Well tolerated (DGAT2 inhibitor) [423]
Monoacylglycerol O-acyltransferase 2 (MGAT2) inhibitor	Facilitates the absorption of dietary fat in the small intestine Interferes with triglyceride resynthesis in the small intestine Plays a role in hepatic lipid metabolism [424,425]	Agent type: energy storage MGAT2 inhibitor BMS-963272 (phase I) S-309309 [273] JTP-103237 (preclinical) [424,426,427]	Not known to date
Fat absorption	Reduces fat absorb-tion by up to 30% [287,428]	Agent type: energy absorption Intestinal lipase inhibitor Orlistat * approved in 1999 (FDA), 1998 (EMA) for long time use Inhibits pancreatic and gastric lipase Cetilistat (phase II)	Oily rectal leakage, abdomi-nal distress, abdominal pain, flatulence with discharge, fecal urgency, steatorrhea, fecal incontinence, and increased defecation [286,289] Better tolerance of cetilistat compared to orlistat [294]
Nutrients absorption	Mechanical mode of action Composed of modi-field cellulose cross-linked with citric acid that absorbs water to occupy about one-fourth of the average stomach volume, promoting fullness [287]	Agent type: energy absorption Hydrogel matrix Gelesis100 (FDA approved in 2019 for adults with a BMI of at least 25 kg/m2, with or without comorbidities) [429,430]	Side effects: abdominal dis-tension, infrequent bowel movements, and dyspepsia [287] Should be considered food when administered simultaneously with drugs [287,431]

* Drugs in current use.