Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas

Table 1 Summary of evidence on PPARs agonists on metabolic outcomes in clinical and experimental studies

Model	PPAR agonist	Effect/mechanism	Ref.
HF diet fed C57BL/6 mice (14 wk)	WY14643 (3.0 mg/kg BM)	Decreased body mass and increased hepatic beta-oxidation	Barbosa-da-Silva et al[57], 2015
HF diet fed C57BL/6 mice (14 wk)	WY14643 (2.5 mg/kg BM)	Decreased insulin, hepatic steatosis, and enhanced mitochondria per area of liver tissue	Veiga et al[58], 2017
HF diet fed C57BL/6 mice (14 wk)	WY14643 (2.5 mg/kg BM)	Browning of subcutaneous WAT, increased thermogenesis	Rachid et al[59], 2018
HF diet or high-fructose-fed C57BL/6 mice (17 wk)	WY14643 (3.5 mg/kg BM)	Reduced whitening in HF-fed mice via increased VEGFA and reduced inflammation	Miranda et al[62], 2020
HF diet fed C57BL/6 mice (15 wk)	Fenofibrate (100.0 mg/kg BM)	Increased irisin-Pgc1α-Prdm16 and induced thermogenic beige adipocytes	Rachid et al[63], 2015
High-fructose diet-fed C57BL/6 mice (11 wk)	GW501516 (3.0 mg/kg/d)	Potent anti-inflammatory effects that reversed adipocyte hypertrophy	Magliano et al[64], 2015
Knockout mice for Pparγ in collecting duct	Rosiglitazone (320.0 mg/kg diet)	PPARγ regulates sodium transport in the collecting ducts and mediates the rosiglitazone-induced edema	Zhang et al[77], 2005
Human subcutaneous white adipose tissue biopsy	Pioglitazone (45 mg daily for two months)	Pioglitazone reduced CD68 and MCP-1 expression in adipose tissue, improving insulin sensitivity	Di Gregorio et al[78], 2005
HF diet fed C57BL/6 mice (16 wk)	Tesaglitazar (4 mg/kg BM)	PPARα/γ synergism treated dysbiosis and favored thermogenesis	Miranda et al[80], 2023
Human jejunal biopsies	Cells treated with GW7647 (600 nM) or GFT505 (1 μM) for 18 h	Intestinal PPARα activation induces HDL production	Colin et al[82], 2013
Knockout mice	25.0% fish oil in the diet	Increased adiponectin, improved glucose metabolism, and islet hypertrophy	Nakasatomi et al[112], 2018
Non-obese diabetic mice	0.1% fenofibrate in the diet	Anti-inflammatory, antiapoptotic effects, and enhanced islet innervation, ameliorating glucose handling	Holm et al[114], 2019
Monosodium glutamate induced obese rats	100 mg/kg fenofibrate for 12 wk	Long-term treatment disrupted beta cell function due to increased NF-κB and iNOS expression	Liu et al[115], 2011
Rat pancreatic islets in vitro	300 microM bezafibrate for 8 h	Bezafibrate enhanced GSIS through Pparα activation in short-term culture. Long-term culture caused beta cell dysfunction due to overstimulation	Yoshikawa et al[116], 2001
Diabetic subjects	400 mg bezafibrate for two years	Bezafibrate avoided the progressive decline of beta cell function and insulin resistance increase	Tenenbaum et al[117], 2007
Subjects diagnosed with type 2 diabetes and dyslipidemia	Pioglitazone 30 mg/d for 12 wk and 45 mg/d for additional 12 wk; rosiglitazone 4 mg/d for 12 wk and 8 mg/d for additional 12 wk	Pioglitazone had better effects regarding improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size	Goldberg et al[127], 2005
db/db mice	Pioglitazone 15 mg/kg BM for 18 d	Restoration of pancreatic islet function with increased expression of insulin and NK6 Homeobox 1 expression	Collier et al[132], 2021
Knockout-Ay mice	High-fat diet plus pioglitazone 0.02% for 6 wk	Islet preservation through ER stress and inflammation alleviation	Hong et al[133], 2018
Diabetic Wistar rats (low streptozotocin dose)	10 mg/kg pioglitazone or vildagliptin or their combination for 4 wk	Vildagliptin maximized pioglitazone effects on inflammation and oxidative stress attenuation	Refaat et al[134], 2016
Type 2 diabetic patients	Sitagliptin 100 mg/d or Pioglitazone 30 mg/d or their combination for 12 wk	Both drugs exerted complementary effects on blood glucose control	Alba et al[135], 2013
Non-diabetic hypertensive subjects	Telmisartan (80 mg/d) for 6 wk	Telmisartan enhanced insulin sensitivity in hypertensive patients independent of adiponectin induction	Benndorf et al[136], 2006
High-fat diet-fed mice (16 wk)	Telmisartan (5 mg/kg BM) alone or in combination with sitagliptin (1 g/kg BM) or metformin (300 mg/kg BM)	Treated animals exhibited marked mitigation of hepatic steatosis and islet hypertrophy; telmisartan combination with sitagliptin normalized alpha and beta cell mass	Souza-Mello et al[93], 2010; Souza-Mello et al[97], 2011
High-fat diet-fed mice (15 wk)	Telmisartan (10 mg/kg)	Amelioration of endocrine pancreas structure and function, with enhanced islet vascularization and reduced apoptosis rate	Graus-Nunes et al[96], 2017
db/db mice	Telmisartan (3 mg/kg BM), linagliptin (3 mg/kg BM) or their combination for eight weeks	Combined therapy provided better results than the monotherapies on glucose homeostasis, islet cell functions, and structure via reduced oxidative stress	Zhao et al[137], 2016
High-fat-fed foz/foz obese/diabetic mice for 16 wk	WY14643 (0.1% w/w) for 10 d or 20 d	PPARα activation mitigated steatosis, and hepatocyte ballooning, besides reducing NF-κB and JNK activation. Persistent adipose-derived MCP1 enhanced levels may limit its property to treat NASH	Larter et al[171], 2012
High-fructose diet-fed mice (17 wk)	WY14643 (3.5 mg/kg BM) or linagliptin (15.0 mg/kg BM) or their combination	The WY14643 monotherapy or its combination with linagliptin-treated dysbiosis, controlling endotoxemia and mitigating liver steatosis	Silva-Veiga et al[173], 2020
Type 2 diabetic patients	Metformin 2 g/d + Pioglitazone (15 mg/d, 30 mg/d, or 45 mg/d)	All pioglitazone doses exerted similar effects, with mitigation of liver steatosis and inflammation, with improved systemic insulin resistance	Della Pepa et al[182], 2021
CCl4-injured mice	Rosiglitazone (5 mg/kg BM) for two weeks	Rosiglitazone blocked liver fibrosis progression through the down-regulation of fibrogenic genes and HSCs inactivation	Liu et al[185], 2020
Patients with NAFLD/NASH	Saroglitazar 1 mg, 2 mg, or 4 mg for 16 wk	Saroglitazar 4 mg significantly mitigated insulin resistance and atherogenic dyslipidemia	Gawrieh et al[190], 2021
HF diet fed mice (14 wk)	GW0742 (1 mg/kg BM) for four weeks	PPARβ/δ mitigated hepatic steatosis through improved insulin resistance and ER stress alleviation	Silva-Veiga et al[198], 2018

HF: High-fructose; NAFLD: Non-alcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PPAR: Peroxisome proliferator-activated receptors; WAT: White adipose tissue; ER: Endoplasmic reticulum; NF-κB: Noncanonical nuclear factor-kappaB; HSCs: Hepatic stellate cells; iNOS: Inducible nitric oxide synthase; GSIS: Glucose-stimulated insulin secretion; HDL: High-density cholesterol; LDL: Low-density cholesterol.