An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.

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...

Summary Secretion of Wnts by adipose cells has an important role in the control of murine adipogenesis. We present the first evidence that a Wnt antagonist, Dickkopf 1 (Dkk1), is secreted by human preadipocytes and promotes adipogenesis. DKK1 mRNA increases six hours after onset of human adipogenesis and this is followed by an increase in Dkk1 protein. With further differentiation, the mRNA and protein levels progressively decline such that they are undetectable in mature adipocytes. The transient induction in DKK1 correlates with downregulation of cytoplasmic and nuclear β-catenin levels, this being a surrogate marker of canonical Wnt signalling, and Wnt/β-catenin transcriptional activity. In addition, constitutive expression of Dkk1 in 3T3-L1 preadipocytes promotes their differentiation, further supporting the functional significance of increased Dkk1 levels during human adipogenesis. Concomitant downregulation of the Dkk1 receptors LRP5 and LRP6 is likely to potentiate the ability of Dkk1 to inhibit Wnt signalling and promote differentiation. Notably, Dkk1 is not expressed in primary murine preadipocytes or cell lines. The involvement of Dkk1 in human but not murine adipogenesis indicates that inter-species differences exist in the molecular control of this process. Given the public health importance of disorders of adipose mass, further knowledge of the pathways involved specifically in human adipocyte differentiation might ultimately be of clinical relevance.