Abstract
Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk between leptin and glucose. Glucose starvation blocked the ability of leptin to stimulate tyrosyl phosphorylation and activation of JAK2 and STAT3 in a variety of cell types. Glucose dose-dependently enhanced leptin signaling. In contrast, glucose did not enhance growth hormone-stimulated phosphorylation of JAK2 and STAT5. Glucose starvation or 2-deoxyglucose-induced inhibition of glycolysis activated AMPK and inhibited leptin signaling; pharmacological inhibition of AMPK restored the ability of leptin to stimulate STAT3 phosphorylation. Conversely, pharmacological activation of AMPK was sufficient to inhibit leptin signaling and to block the ability of glucose to enhance leptin signaling. These results suggest that glucose and/or its metabolites play a permissive role in leptin signaling, and that glucose enhances leptin sensitivity at least in part by attenuating the ability of AMPK to inhibit leptin signaling.
Highlights
Leptin is a metabolic hormone that is required for the maintenance of normal energy balance and body weight [1]
It is important to identify additional regulators of leptin signaling in order to fully understand energy homeostasis and body weight regulation
We report that glucose is likely to play a permissive role in leptin signaling and to improve leptin sensitivity in a dose-dependent manner
Summary
Leptin is a metabolic hormone that is required for the maintenance of normal energy balance and body weight [1]. Leptin is secreted into the bloodstream from adipose tissues [2]. It suppresses food intake, increases energy expenditure, and promotes weight loss primarily by binding to and activating LEPRb in the hypothalamus [1]. Genetic deficiency of leptin or LEPRb results in hyperphagia and severe obesity in both rodents and humans [2,3,4,5,6]. Circulating leptin levels increase under most obesity conditions [7,8]; diet-induced obesity is associated with a reduced ability of leptin to suppress both food intake and body weight gain [1,7,9]. Leptin resistance is believed to be the primary risk factor for obesity [1]; the underlying molecular mechanisms for leptin resistance remain largely unknown
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