Metformin Restores Leptin Sensitivity in High-Fat–Fed Obese Rats With Leptin Resistance

Abstract

To evaluate whether metformin enhances leptin sensitivity, we measured leptin sensitivity after 4 weeks of metformin treatment (300 mg/kg daily) in both standard chow and high-fat-fed obese rats. Anorexic and fat-losing responses after intracerebroventricular leptin infusion for 7 days (15 g daily per rat) in standard chow rats were enhanced by metformin treatment, and these responses to leptin were attenuated in high-fat-fed obese rats compared with age-matched standard chow rats. However, these responses to leptin were corrected by metformin treatment in high-fat-fed obese rats. Moreover, serum concentrations of leptin and insulin were decreased dramatically by leptin in metformin-treated standard chow and high-fat-fed obese rats. The hypothalamic phosphorylated AMP-activated protein kinase level was decreased by lower leptin dose in metformin-treated rats than in untreated rats. In an acute study, metformin treatment also increased the anorexic effect of leptin (5 g), and this was accompanied by an increased level of phosphorylated signal transducer and activator of transcription 3 in the hypothalamus. These results suggest that metformin enhances leptin sensitivity and corrects leptin resistance in high-fat-fed obese rats and that a combination therapy including metformin and leptin would be helpful in the treatment of obesity. Diabetes 55:716 -724, 2006 L eptin, an adipocyte-derived hormone, contributes to body weight homeostasis by regulating food intake and energy expenditure (1). However, leptin is not widely used in the clinical field because obesity is accompanied by elevated serum leptin and responds poorly to the pharmacological administration of exogenous leptin, which ordinarily potently promotes fat mass loss and body weight reduction in lean subjects (2,3); moreover, this poor response of obese subjects is a characteristic of leptin resistance. Thus, the correction of leptin resistance in obese individuals would allow leptin to be used to treat obesity.Metformin, an oral biguanide insulin-sensitizing agent, inhibits hepatic glucose production, enhances the effects of insulin on glucose uptake in skeletal muscles and adipocytes, and decreases intestinal absorption of glucose (4 -7). It is also well known that metformin administration reduces body weight (8,9). Moreover, metformin decreases leptin concentration in morbidly obese subjects (9,10) and in normal-weight healthy men (11). Although leptin concentration is closely related to body fat mass, the leptin-reducing effect of metformin cannot be fully explained by body weight reduction because metformin reduces leptin level even without changing body weight in normal-weight healthy men (11). However, the mechanisms by which metformin reduces body weight and leptin concentration are poorly understood. In addition, it has been recently reported that metformin targets AMP-activated protein kinase (AMPK), which is also activated by leptin (12-14). The above findings imply that a more delicate interaction takes place between metformin and leptin. We h...

Leptin Resistance and Obesity

“…Administration of metformin restores leptin sensitivity in high fat-fed obese rats with leptin resistance [88]. Metformin treatment increased cerebrospinal fluid leptin concentrations in both standard and high fat diet-fed obese rats.…”

“…These findings suggest the concept that improvement of the transport of leptin into the brain may correct leptin resistance in the rats with DIO after metformin administration. Thus, combined treatment with metformin and leptin may be useful in the treatment of obesity [88].…”

Immunohistochemical Detection of FOXP3 Shows Stimulatory Effect of Metformin on Thymus Regulatory T-Cells in Type 2 Diabetic Mice

“…Previous studies have shown that metformin treatment can enhance central and peripheral leptin receptor availability and increases its signal transduction in HFD-fed obese animals and in aged obese non-diabetic animals as well 19 .…”

Critically Discuss the Revival of Leptin for Obesity Therapy

“…Likewise, several research groups have investigated blocking those negative regulators of leptin signalling such as SOCS3 and the phosphor-tyrosine protein phosphatase PTP 1B to improve the leptin response in obese persons (Kaszubska et al, 2002;Reed et al, 2010;Roujeau et al, 2014). Furthermore, co-administration of leptin with either exendin-4 or FGF21 has been shown to restore leptin responsiveness in diet-induced obese mice (Kim et al, 2006;Müller et al;.…”

“…In addition, gastrointestinal derived peptides and a series of already approved pharmaco therapies have been found to amplify the weight-lowering actions of exogenous leptin (Wang et al, 2000;Kim et al, 2006;Roth et al, 2008;Unniappan & Kieffer, 2008;Müller et al, 2012). Likewise, several research groups have investigated blocking those negative regulators of leptin signalling such as SOCS3 and the phosphor-tyrosine protein phosphatase PTP 1B to improve the leptin response in obese persons (Kaszubska et al, 2002;Reed et al, 2010;Roujeau et al, 2014).…”