Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.

The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice are dependent on LXRs and correlate with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the roles of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligandregulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. T he liver plays a central role in the control of whole-body lipid homeostasis, and hepatic lipid metabolism is continuously adjusted to fit the needs of the organism. This adaptation requires major adjustments in the hepatic metabolic gene program, including a strong upregulation of lipogenic gene expression in the fed state, whereas in the fasting state, the expression of genes involved in fatty acid oxidation as well as ketogenesis and hepatic glucose production is highly induced. Class II nuclear receptors (NRs), i.e., NRs forming heterodimers with retinoid X receptor (RXR), play a key role in coordinating these changes. They include the liver X receptor (LXR) (29, 57) and peroxisome proliferatoractivated receptor (PPAR) (32, 34, 41) families as well as farnesoid X receptor (FXR) (44, 55, 88), pregnane X receptor (PXR) (5, 33), vitamin D receptor (VDR) (43), constitutive androstane receptor (CAR) (3, 9, 23), and retinoic acid receptors (RARs) (13).The LXR family consists of the two subtypes, LXR␣ (NR1H3) and LXR␤ (NR1H2), both of which form obligate heterodimers with RXR. LXR-RXR heterodimers are reported to bind to LXR response elements (LXREs) that consist of a direct repeat of the core sequence 5=-AGGTCA-3= spaced by 4 nucleotides (DR4) (2,72,76,79,92). LXRs are activated by oxidized cholesterol derivatives and play an important role in the regulation of cholesterol homeostasis in the liver. Thus, pharmacological activation of LXR leads to the induction of several genes implicated in reverse cholesterol transport and mobilization of cholesterol, such as the ATP binding cassette (ABC) transporter genes Abca1, Abcg1, Abcg5, and Abcg8 and the apolipoprotein E gene (ApoE) (12,31,37,60,63,84). Furthermore, a recent genomewide study of LXR in human hepatoma cells showed that LXR also downregulates expression of the cholesterologenic genes for lanosterol 14␣-demethylase (Cyp51A1) and squalene synthase (Fdst1) (89). Moreover, LXR activation induces triglyceride synthesis partly through induction of the lipogenic transcription factors sterol regulatory element-binding protein 1c (SREBP-1c) (42,61,95) and carbohydrate response element-binding protein (ChREBP) (8) but also by direct activation of genes encoding lipogenic enzymes such as fatty acid synthase (Fasn), stearoyl coenzyme A (CoA) desaturase (Scd1), ...