The Link Between Nutritional Status and Insulin Sensitivity Is Dependent on the Adipocyte-Specific Peroxisome Proliferator–Activated Receptor-γ2 Isoform

Abstract

The nuclear receptor peroxisome proliferator-activated receptor-␥ (PPAR␥) is critically required for adipogenesis. PPAR␥ exists as two isoforms, ␥1 and ␥2. PPAR␥2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPAR␥1. To elucidate the relevance of the PPAR␥2 in vivo, we generated a mouse model in which the PPAR␥2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the ␥2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPAR␥2 is not the result of lipodystrophy and suggests a specific role for PPAR␥2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPAR␥2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPAR␥2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPAR␥2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism. Diabetes 54: 1706 -1716, 2005 P eroxisome proliferator-activated receptor-␥ (PPAR␥) plays a central role in adipogenesis and insulin sensitivity. PPAR␥ is expressed as two isoforms, PPAR␥1 and PPAR␥2, which differ only in that PPAR␥2 has 30 extra amino acids at its NH 2 terminus. Under physiological conditions, PPAR␥2 is expressed almost exclusively in white and brown adipocytes, whereas PPAR␥1 is also expressed in colon, macrophages, skeletal muscle, and liver (1). Although there is limited information regarding the functional differences between these two splice variants, PPAR␥2 may be more adipogenic than PPAR␥1 (2,3). PPAR␥2 may play a distinct role in regulating insulin sensitivity as suggested by the strong epidemiological evidence that the PPAR␥2-specific Pro12Ala variant influences diabetes susceptibility in humans (4).We have shown that expression of PPAR␥ isoforms is differentially regulated by nutritional factors (5). Murine studies showed that PPAR␥2 mRNA is markedly downregulated in white adipose tissue (WAT) by fasting and normalized by re-feeding (1). Similarly, PPAR␥2 gene expression is increased in WAT by a high-fat diet (HFD) as well as in mouse models of diet-induced obesity (5). Studies using genetically modified mouse models have addressed the role of PPAR␥ in vivo (6). A proadipogenic role for PPAR␥ in vivo was supported by the global PPAR␥-deficient and the hypomorphic PPAR␥ mouse models (7-9). In addition to a role in promoting adipogenesis, activation of PPAR␥ also improves insulin sensitivity (10). However, the characterization of the heterozygous PPAR␥ knockout mouse provided the paradoxical finding that mice with a 50% reduction in PPAR␥ gene dosage were resistant to HFD-induced ob...

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

“…Dual-energy X-ray absorptiometry (DEXA; Lunar Corporation, www.lunarcorp.com) was used to measure body composition. Oxygen consumption was measured in 24-wk-old transgenic and WT mice from the HFD cohort after an overnight fast, by an OXYMAX System 4.93 indirect calorimeter (Columbus Instruments) as described previously (48). Body temperature values represent the mean of four rectal temperature measurements over a 2-wk interval between 1400 hours and 1600 hours with a TES-319 digital thermometer (TES Electronic Corp.).…”

Dietary polyunsaturated fatty acids and the Pro12Ala polymorphisms of PPARG regulate serum lipids through divergent pathways: a randomized crossover clinical trial

“…Accordingly, animal studies suggest a complex interaction between PPARG2 and dietary fat. Mice lacking the PPARG2 isoform are more insulin-resistant compared to wild-type mice on normal chow diet but not on high-fat diet (Medina-Gomez et al 2005). Furthermore, in Pro12Ala knock-in mice, the beneficial effects of the Ala12 allele on adiposity, plasma lipids, and insulin sensitivity are lost with a high-fat diet (Heikkinen et al 2009).…”

Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

“…Of the two known PPARγ isoforms, PPARγ1 is widely distributed in tissues, whereas PPARγ2 is more specific to adipose tissues. We previously generated a mouse model of PPARγ2 deficiency (PPγ2KO) (11), which is insulin resistant and presents adipose tissue dysfunction, particularly when challenged with positive energy balance (12). Moreover, PPARγ2 seems to be important for pancreatic β-cell mass adaptation in murine models of the metabolic syndrome (13,14).…”