Table 2.

Description of in vivo/in vitro mechanisms involved in the decreased incidence of metabolic disorders.

Compound	Model	Treatment Time	Doses/Concentration	Biological Activity	Reference
Iso-humulone Iso-cohumulone Iso-adhumulone	CV-1 cells		Iso-humulone/iso-cohumulone/iso-adhumulone 1‒3‒10 μM	↑PPAR- $\gamma$	[24,26]
	HepG2 cells		Iso-humulone/iso-cohumulone/iso-adhumulone 3‒10‒30 μM	↑PPAR-α
	KK-Ay male mice	2 weeks	HFD + 0.18% (w/w) iso-humulone/iso-cohumulone	↓plasma triglycerides ↓free fatty acid ↑glucose tolerance ↓fasting plasma insulin levels ↓IR index ↓body weight ↑liver ACO gene expression ↑liver FAT gene expression ↓white adipose tissue ADRP gene expression ↓white adipose tissue LPLgene expression
	C57BL/6N female mice	10 weeks 14 days	HFD + 0.18% (w/w) iso-humulone/iso-cohumulone HFD +10–100 mg/kg/day iso-humulone/iso-cohumulone
IHE (iso-humulone, iso-cohumulone, and iso-adhumulone)	C57BL/6NCrj mice PPARα-/-/129S4/SvJae mice	1 week	AIN76A + 1% IHE/AIN76A + 2% Chol + 1% IHE	↓plasma triglycerides ↓nonesterified free fatty acid ↑PPAR-α ↑microsomal ω-oxidation ↑peroxisomal β-oxidation ↑mitochondrialβ-oxidation	[28]
IHE (iso-humulone, iso-cohumulone, and iso-adhumulone)	HepG2 cells		90 μg/mL	↑PPAR-α	[32]
	C57BL/6N female mice	6 weeks 5 weeks	HFD + 0.2–0.6% IHE AIN93G standard diet + 0.2–0.6% IHE/HFD + 0.2–0.6% IHE	↓body weight ↓plasma triglycerides ↑glucose tolerance ↑faeces lipid content ↓pancreatic triacylglycerol lipase activity ↑liver ACO gene expression ↑liver MCAD gene expression ↓ liver DGAT2 gene expression
	KK-Ay male mice	5 weeks	HFD + 0.2–0.6% IHE
	Wistar rat		HFD + 1% IHE
HE	Cloned mouse 3T3-L1 fibroblasts C57BL/6J male mice C57BL/6 ovariectomized female mice	20 weeks 12 weeks	0–500 µ/mL HE HFD + 2 or 5% HE 400 mg/kg HE	↑PPAR- $\gamma$ expression ↓body weight ↓liver weight ↓mesenteric adipose tissue weight ↓epididymal adipose tissue weight ↓PPAR-$\gamma$ expression ↓liver TC ↓liver lipids (TC and TAG) ↓plasma lipids (TC and TAG) ↓plasma glucose levels	[29,33]
IHE1 (humulones, lupulones and iso-humulones) IHE1 (iso-humulones) Purified iso-humelones	C57BL/6NCrj female mice	Experiment1 1 week 2 week Experiment2 1 week Experiment3 2 week Experiment4 1 week	Atherogenic diet Atherogenic diet + 2 mL IHE1/kg Atherogenic diet + 5 mL IHE1/kg Atherogenic diet + 10 mL IHE2/kg Basal diet Basal diet + 10 mL IHE2/kg Cholesterol diet + 10 mL IHE2/kg Cholesterol diet Cholesterol diet + 0.5 g Fenofibrate Cholesterol diet + 10 mL IHE2/kg Cholesterol diet Cholesterol diet + 10 mL IHE2/kg Cholesterol diet + 3 g purified iso-humulones	↓body weight ↑HDL-cholesterol ↓plasma triacylglycerol levels ↑ACO mRNA levels ↑ACS mRNA levels ↑LPL mRNA levels ↑FATP mRNA levels ↑HMGS mRNA levels ↑LDLR mRNA levels ↓Apo AI mRNA levels ↓Apo CIII mRNA levels	[44]
Iso-humulone	PHH cells HSC cells		5–10–20 μg/mL	↑PPAR-α ↑PPAR-$\gamma$ expression in HSCs cells$\gamma$ expression in PHH cells ↓SCD1 expression ↓FASN expression ↑CPT1 expression ↑ACOX1 expression	[27]
	C57BL/6N mice	15 weeks	WTD + 0.5%(w/w) iso-humulone	↓weight gain↓adipose tissue expansion ↓leptin ↑adiponectin ↓insulin resistance $\gamma$ expression ↑mitochondrial β-oxidation ↓HMOX1 expression ↓SCD1 expression ↓FASN expression ↓JNK pathway
THIAA	C57BL/6J mice	8 weeks	HFD + 0.1% THIAA	↓body weight ↓total adiposity ↓subcutaneous and visceral adipose depots ↑glucose homeostasis ↓hyperinsulinemia ↑IAP activity ↑ZO-1 mRNA levels ↑occludin m-RNA levels	[34]
THIAA	C57Bl/6J male mice	14 weeks	HFD + 100 mg/kg THIAA	↓ weight gain ↓total body fat ↑glucose tolerance ↓fasting insulin levels	[35]
KDT501	THP-1 cells 3T3L1 murine preadipocytes Human subcutaneous adipocytes C57Bl/6J male mice ZDF male rats	30 days 32 days	6.25, 12.5, 25, 50 µM 3.13, 6.25, 12.5, 25 µM 10 µM 25, 50, 100 and 200 mg/kg KDT501 100, 150, or 200 mg/kg KDT501	$\gamma$↓MCP-1 ↓RANTES ↓IL-6 ↓fat mass ↓glucose AUC ↓cholesterol ↓thriglycerides	[71]
THIAA	RAW264.7 macrophages		1–5–10–20 µg/mL	↓PEG2 production ↓COX-2 protein abundance ↓NO formation ↓NF-kB nuclear abundance and activity ↓BKT (IC50 =41 µg/mL) ↓SyK (IC50 = 60 µg/mL) ↓BMX (IC50 = 87 µg/mL) ↓PI3K (β, IC50 = 54 µg/mL; δ$\mathrm{and} –\gamma$, IC50 = 15 µg/mL) ↓PDK1 (IC50 = 53 µg/mL) ↓PKBβ (IC50 = 87 µg/mL) ↓GSK3(α, IC50 = 28 µg/mL; β, IC50 = 17 µg/mL)	[53]
Iso-humulone	L929sA mouse fibrosarcoma cells		50–100 μM	↓IL6 protein expression ↓TNF-α protein expression ↓RANTES protein expression ↓NF-kB-dependent gene expression ↓AP-1-driven gene expression ↓CREB-driven gene expression	[45]
RIAA and THIAA	RAW264.7macrophages		1–2.5–5–10–20 µg/mL	↓NF-kB nuclear abundance and activity ↓PEG2 production ↓COX-2 protein abundance ↓TNF-α production ↓iNOS expression ↓NO production ↓BKT ↓SyK	[50]
	DBA/1J female mice	14 days	10–50–250 mg/kg	↓arthritis index ↓joint degradation
RIAA	RAW 264.7 macrophages		1–5–10–20 µg/mL	↓PEG2 production ↓iCOX-2 protein abundance	[59]
THIAA	THP-1 cells HAEC cells		1–5–10–20 µg/mL	↓IL6 expression ↓TNF-α expression ↓RANTES expression ↓MCP-1 expression ↓MMP-9 expression ↓NF-kB activation ↓AP-1 activation ↓monocyte-endothelial cell interaction	[56]
IAA-rich extract	J774 A.1 murine macrophages		25 mg/mL	↓iNOS expression ↓NO production ↓IL6 expression ↓TNF-α expression	[48]
	C57Bl/6 J female mice	4 days	0.75 mg/kg	↓plasma triglycerides ↓iNOS expression
IHE Iso-humulones	RAW264.7 cells Male Fischer rats	2 weeks	2.5, 5 µg/mL iso-humulones 10, 25 µg/mL IHE AIN-76A + 0.01%, 0.04%, 0.05% IHE	↓PEG2 production	[57,58]

Abbreviations: Isomerized hop extract IHE; Hop extract HE; iso-α-acids IAA; Rho-iso-α-acids RIAA; Tetrahydro-iso-α-acids THIAA; Potassium salt of the n-(isobutyl) congener of a tetrahydro iso-α-acid KDT501; High-fat diet HFD; Western type diet WTD.