Hyperleptinemia Precipitates Diet-Induced Obesity in Transgenic Mice Overexpressing Leptin

Abstract

Transgenic mice overexpressing leptin backcrossed to the C57BL/6J genetic background (LepTg) have a lean phenotype, characterized by a 95% reduction in adipose mass; reduced plasma levels of glucose, triglycerides, insulin, and IGF-1; and a 75% decrease in adipocyte size. High-fat diet treatment for 20 wk revealed that, compared with normal mice, the LepTg mice had an increased susceptibility to diet-induced obesity, as demonstrated by their rate of weight gain, higher accumulation of sc white adipose tissue mass, hypertrophy of adipocytes, and normalization of their reduced metabolic parameters. The stromal vascular fraction of white adipose tissue from the LepTg mice was highly cellular and contained cells capable of rapid lipid accumulation in primary cultures. The precipitous diet-induced obesity of the LepTg mice was accompanied with 10-fold and 1.6-fold elevations in insulin and IGF-1, respectively, suggesting that the trophic action of insulin and IGF-1 on the preadipocytes and small adipocytes may have caused them to rapidly differentiate and accumulate triacylglycerol stores. Other contributing factors may involve a shift in insulin sensitivity triggered by hyperleptinemia and a decrease in energy expenditure. These studies demonstrate that a chronic response to hyperleptinemia as in the LepTg mice is a predisposing factor to diet-induced obesity and suggest that individuals who are particularly lean because of increased leptin secretion may develop rapid obesity under conditions of a high-fat diet.

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

“…Leptin resistance is the trademark of diet-induced obesity in rodents [3,4,17] and is generally considered a consequence rather than a cause of obesity. This simple view seems to be at odds with a recent study in transgenic mice overexpressing leptin [26]. The transgenic mice had chronically elevated serum leptin, yet they demonstrated increased weight gain and adiposity when given a high-fat diet, implying a potential interaction between leptin overexpression and high-fat feeding.…”

The Use of Animal Models to Dissect the Biology of Leptin

“…This effect would be most noticeable in animals with no or little fat (e.g., LepTg mice). Thus, generation of LepTg mice with no ␤3AR resulted in a lean phenotype similar to that of LepTg mice with ␤3AR, as judged by their growth curves (Ke et al, 2003) (Figure 6). This infers a normal response of adipocytes to leptin-mediated SNS activation of lipolysis.…”

“…In LepTg mice, the extent of this effect correlated with transgenic leptin levels and varied from a small fat mass (Qiu et al, 2001b) to a virtual absence (Chen et al, 1996;Ogawa et al, 1999), reflecting quantitative effects of leptin on the fat mass. When adipose tissue could be recovered, histological analysis revealed that, compared to normal mice, LepTg adipocytes were 4-fold smaller and were either depleted of triacylglycerol stores or contained minute lipid droplets (Qiu et al, 2001b;Ogus et al, 2003). Whether these small cells represent preadipocytes, adipocytes, or a mixture of both remains to be determined.…”

“…This suggests that the majority of these cells consist of mature adipocytes, albeit without visible intracellular lipids. Recovery and growth of these adipocytes in vitro in a medium rich in glucose, insulin, and insulin-like growth factor-1 (IGF-1), which are all significantly decreased in LepTg mice, revealed a rapid accumulation of triacylglycerols, suggesting a heightened sensitivity to lipid accumulation (Ogus et al, 2003).…”

Les tanycytes hypothalamiques

“…Cependant, pour des raisons qui ne sont pas encore totalement expliquées, cette leptinémie éle-vée ne s'accompagne ni d'une faible prise alimentaire ni d'une forte dépense énergétique [7]. De manière similaire dans les modèles animaux, l'hyperleptinémie induite par un régime riche en graisses (high fat diet ou HFD) aggrave la prise de poids et les anomalies méta-boliques [8]. De plus, l'injection de leptine exogène, même à dose élevée, n'entraîne pas de diminution de la prise alimentaire ni du poids corporel en cas d'obésité chez les animaux et l'humain, sauf dans les rares cas de déficience en …”