Peroxisome proliferator–activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPARα mediates the hypolipidemic action of fibrates, PPARγ is the receptor for the antidiabetic glitazones. PPARα is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the β-oxidative degradation of fatty acids. PPARγ is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPARβ/δ is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPARα controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPARα and PPARγ regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.

Objective: The consumption of fruits is strongly associated with better health and higher bacterial diversity in the gut microbiota (GM). Camu camu ( Myrciaria dubia ) is an Amazonian fruit with a unique phytochemical profile, strong antioxidant potential and purported anti-inflammatory potential. Design: By using metabolic tests coupled with 16S rRNA gene-based taxonomic profiling and faecal microbial transplantation (FMT), we have assessed the effect of a crude extract of camu camu (CC) on obesity and associated immunometabolic disorders in high fat/high sucrose (HFHS)-fed mice. Results: Treatment of HFHS-fed mice with CC prevented weight gain, lowered fat accumulation and blunted metabolic inflammation and endotoxaemia. CC-treated mice displayed improved glucose tolerance and insulin sensitivity and were also fully protected against hepatic steatosis. These effects were linked to increased energy expenditure and upregulation of uncoupling protein 1 mRNA expression in the brown adipose tissue (BAT) of CC-treated mice, which strongly correlated with the mRNA expression of the membrane bile acid (BA) receptor TGR5. Moreover, CC-treated mice showed altered plasma BA pool size and composition and drastic changes in the GM (eg, bloom of Akkermansia muciniphila and a strong reduction of Lactobacillus ). Germ-free (GF) mice reconstituted with the GM of CC-treated mice gained less weight and displayed higher energy expenditure than GF-mice colonised with the FM of HFHS controls. Conclusion: Our results show that CC prevents visceral and liver fat deposition through BAT activation and increased energy expenditure, a mechanism that is dependent on the GM and linked to major changes in the BA pool size and composition.

An increased prevalence of hypertriglyceridemia and gallbladder disease occurs in patients with diabetes or insulin resistance. Hypertriglyceridemia is positively associated to gall bladder disease risk. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays a key role in bile acid and triglyceride homeostasis. The mechanisms controlling FXR gene expression are poorly understood. This study evaluated whether FXR gene expression is regulated by alterations in glucose homeostasis. FXR expression was decreased in livers of streptozotocin-induced diabetic rats and normalized upon insulin supplementation. Concomitantly with diabetes progression, FXR expression also decreased in aging diabetic Zucker rats. In primary rat hepatocytes, d-glucose increased FXR mRNA in a dose- and time-dependent manner, whereas insulin counteracted this effect. Addition of xylitol, a precursor of xylulose-5-phosphate, to primary rat hepatocytes increased FXR expression to a comparable level as d-glucose. Finally, expression of the FXR target genes, SHP and apolipoprotein C-III, were additively regulated by d-glucose and FXR ligands. This study demonstrates that FXR is decreased in animal models of diabetes. In addition, FXR is regulated by glucose likely via the pentose phosphate pathway. Dysregulation of FXR expression may contribute to alterations in lipid and bile acid metabolism in patients with diabetes or insulin resistance.