Obesity is associated with leptin resistance, which alters fuel partitioning. Because this condition is also associated with increased activity of the endocannabinoid system, Buettner et al. sought to investigate whether central leptin could restrain peripheral endocannabinoid tone. Although central leptin had previously been shown to decrease food intake and hepatic glucose production via signal transducer and activator of transcription-3 (STAT-3), the authors reported an important crosstalk between the hypothalamus and adipose tissue lipogenesis by showing that central leptin inhibits adipose tissue lipogenesis via STAT-3 independent mechanisms. Moreover, they provided evidence that on top of its action on lipogenesis, central leptin might decrease endocannabinoid tone in adipose tissue by downregulating anandamide levels, which might further decrease food intake. In opposition, they showed that the ability of hypothalamic leptin to suppress adipose tissue lipogenesis was lost upon sympathetic denervation of adipose tissue or when hypothalamic phosphoinositide 3-kinase signalling was prevented. These observations shore up the important role of the brain in adipose tissue metabolism by showing that the increased endocannabinoid tone observed in obesity is associated with a failure of hypothalamic leptin to restrain peripheral endocannabinoids.
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