Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy

Abstract

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Interestingly, transplantation of white adipose tissue from wild-type mice to these lipodystrophic mice leads to an improvement in insulin sensitivity (Kim et al, 2000a). Similar results are observed with leptin administration (Shimomura et al, 1999). In line with these studies, investigations in humans with lipodystrophia revealed that although visceral or peripheral fat were almost absent, these patients developed NAFLD and hepatic insulin resistance (Petersen et al, 2002;Savage et al, 2005).…”

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

“…Previously, we and others have demonstrated that food intake reduction alone was insufficient for improving glucose and lipid metabolism [6,10,12]. It has also been reported that fasting insulin and triacylglycerol levels increased within several days after withdrawal of leptin administration even though the level of food intake remained constant in the patients with lipodystrophy [13].…”

“…Given the glucose-lowering action of leptin, we and others have demonstrated that leptin infusion or transgenic overexpression of leptin reverses metabolic abnormalities in different mouse models of lipodystrophy [10,12]. Recently, we and others confirmed that leptin treatment effectively reduces food intake and improves hyperglycaemia, hypertriacylglycerolaemia and fatty liver in patients with lipoatrophic diabetes [13][14][15][16].…”

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

“…This is corroborated by recent clinical and animal investigations that excess as well as complete absence of fat in the body are concomitant with hyperinsulinemia, insulin insensitivity and diabetes. 7,[22][23][24][25][26][27][28] The discovery of insulin in 1922 and the subsequent development of insulin analogs have been the life-saving treatments of hyperglycemia and in delaying or preventing the array of chronic complications of diabetes mellitus. 2,13,[29][30][31] Diabetes, therefore, has traditionally been viewed as an affliction of either lack of or incomplete use of insulin and, consequently, conventional research has focused entirely on improving ways to deliver insulin for precision in attaining glycemic control to simulate the physiological range of blood glucose, necessary to combat the comorbidity cluster of this chronic malady.…”