Adipocyte-selective Reduction of the Leptin Receptors Induced by Antisense RNA Leads to Increased Adiposity, Dyslipidemia, and Insulin Resistance

Abstract

Although recent evidence suggests that leptin can directly regulate a wide spectrum of peripheral functions, including fat metabolism, genetic examples are still needed to illustrate the physiological significance of direct actions of leptin in a given peripheral tissue. To this end, we used a technical knock-out approach to reduce the expression of leptin receptors specifically in white adipose tissue. The evaluation of leptin receptor reduction in adipocytes was based on real time PCR analysis of the mRNA levels, Western blot analysis of the proteins, and biochemical analysis of leptin signaling capability. Despite a normal level of leptin receptors in the hypothalamus and normal food intake, mutant mice developed increased adiposity, decreased body temperature, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated hepatic and skeletal muscle triglyceride levels. In addition, a variety of genes involved in regulating fat and glucose metabolism were dysregulated in white adipose tissue. These include tumor necrosis factor-␣, adiponectin, leptin, fatty acid synthase, sterol regulatory element-binding protein 1, glycerol kinase, and ␤ 3 -adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high fat feeding with regard to developing obesity and severe insulin resistance. Thus, we provide a genetic model demonstrating the physiological importance of a peripheral effect of leptin in vivo. Importantly, this suggests the possibility that leptin resistance at the adipocyte level might be a molecular link between obesity and type 2 diabetes.

Effect of high-fat diet feeding on leptin receptor expression in white adipose tissue in rats: depot- and sex-related differential response

“…Conversely, in female rats, OB-Rb mRNA levels increased under HF-diet, and this allowed the maintenance of fatty acid oxidation capacity (as suggested by the maintenance of PPARa and CPT1 mRNA expression levels). Adipocyteselective reduction of the OB-Rb has been associated with obesity and type 2 diabetes [7]. We have previously described that male rats fed with an HF-diet have increased serum insulin levels and obesity-linked disorders, such as fat accumulation in the liver, while female rats did not present, at least to this extent, these metabolic complications [16].…”

“…In fact, the role of leptin on white adipose tissue (WAT) has been reported to be essential in modulating the adipocytes' metabolic function [25], up-regulating fat oxidation [13] and decreasing lipogenesis [27]. In this way, it has been postulated that the peripheral effects of leptin, such as in WAT, may also help regulate the entire body weight [7].…”

“…In human studies, morbid obesity has been associated with a lower OB-Rb mRNA abundance in the subcutaneous adipose depot when compared with lean subjects [20]. In addition, fat tissue-specific leptin resistance has been described to be one of the primary causes of insulin resistance [7]. Thus, peripheral leptin resistance may be a major contributing factor for the development of obesity and its associated disorders.…”

Leptin intake during the suckling period improves the metabolic response of adipose tissue to a high-fat diet

“…This pivotal function of the adipose tissue under conditions of high fat influx has been previously suggested. 39 Leptin resistance in WAT has been associated with insulin resistance and dyslipidemia, 11 in fact this has been proposed to be the major contributing factor to the insulin resistance observed in obese subjects. 11 Our study results support this hypothesis showing that the expression levels of some genes regulated by insulin, such as GLUT4, are downregulated in control animals under HF-diet feeding in the same fat depots (mesenteric and retroperitoneal) in which a decrease in leptin receptor levels is also observed.…”

“…9,10 Its importance has been reinforced by studies of adipocyte-specific reduction of the expression of the leptin receptor in mice by antisense RNA. 11 These mice showed an obese phenotype, with increased adiposity, dyslipidemia and insulin resistance, 11 suggesting that the peripheral actions of leptin may also help regulate the entire body weight and metabolism. Moreover, it has been described that diet-induced obesity in rats produces downregulation of the OB-Rb expression in adipose tissue, producing a leptinergic blockade at peripheral level.…”