Leptin Deficiency Unmasks the Deleterious Effects of Impaired Peroxisome Proliferator–Activated Receptor γ Function (P465L PPARγ) in Mice

Abstract

Peroxisome proliferator-activated receptor (PPAR)␥ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPAR␥ display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPAR␥ developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPAR␥-related findings, bringing into question the relevance of other PPAR␥ murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPAR␥ mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPAR␥ mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPAR␥ mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPAR␥ mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.

Mouse models of inherited lipodystrophy

“…Interestingly they did, however, manifest hypertension, which is common in FPLD3. It was only when these mice were crossed with leptindeficient obese ob/ob mice that extreme insulin resistance was noted (Gray et al, 2006). The same group observed a similarly exaggerated insulin resistance phenotype in Pparg2 isoformspecific knockouts when crossed with ob/ob mice (Medina-Gomez et al, 2007).…”

“…Firstly, as with the LMNA transgenic model discussed above, none of these models accurately mimic the stereotyped pattern of fat loss that is seen in humans with FPLD3. At least two independent groups generated P465L Pparg knock-in mice (Tsai et al, 2004;Gray et al, 2006). This mutation is homologous to the first human PPARG mutation (P467L) associated with partial lipodystrophy (Barroso et al, 1999;Savage et al, 2003).…”

PPARs and adipocyte function

“…Reciprocally, PPAR agonist treatment in humans leads to peripheral redistribution of WAT [27]. Finally, mice harbouring dominant negative PPAR mutations similarly exhibit altered fat pad distribution (albeit one characterised by decreased intra-abdominal relative to extra-abdominal WAT) [28,29] indicating that PPAR also plays a role in determining WAT distribution.…”

“…lower FFA levels in humans and rodents [27]. Furthermore, although protected from obesity leptin deficient (ob/ob) mice which lack PPARγ2 or carry a heterozygous dominant negative PPAR mutation (P465L) develop severe insulin resistance [28,65].…”

Lipodystrophy: metabolic insights from a rare disorder

“…More direct evidence for the need to be able to expand adipose tissue depots in response to sustained positive energy balance comes from the PPARG P465L mouse model. The equivalent human variant is associated with partial lipodystrophy (FPLD3) and severe insulin resistance, but the P465L knockin mice do not manifest insulin resistance unless crossed with severely hyperphagic leptin-deficient ob/ob mice (Gray et al 2006). In the latter context, namely persistent hyperphagia due to the absence of an essential appetite-regulating hormone (leptin), the defect in adipogenesis and adipocyte function induced by the mutation leads to profound metabolic disturbances and severe early onset diabetes.…”