Editors' ChoiceMetabolism

Leptin rocks around the circadian CLOCK

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Science Translational Medicine  29 Jul 2015:
Vol. 7, Issue 298, pp. 298ec131
DOI: 10.1126/scitranslmed.aac9742

Modern lifestyle is associated with longer waking hours and a shift to a more nocturnal schedule. Disruption of the circadian rhythm has been shown to promote obesity and metabolic complications. Recent research has shown that circadian disruption can abolish the normal diurnal variation in serum leptin, independently of changes in external food cues or physical activity. However, the underlying mechanism for this phenomenon and how it leads to weight gain were unknown. Now, Kettner et al. show that the peripheral circadian clock directly regulates leptin transcription in adipose tissue, and that the central circadian clock plays a dominant role in response to leptin signaling. Furthermore, the authors show that circadian disruption induces leptin resistance independent of other risk factors for obesity.

The authors used a mouse jet-lag model to simulate circadian dysfunction and found that chronic jet-lag resulted in high, arrhythmic serum concentrations of leptin, which correlated with weight gain and increased fat mass, but no change in the diurnal profiles of food intake, physical activity, or energy expenditure. At the level of the adipose tissue, jet-lagged mice showed a disruption of circadian leptin expression. The key endogenous clock heterodimer BMAL1/CLOCK was shown to regulate leptin transcription through C/EBPα, and the circadian rhythm of this regulation was achieved through a differential effect of low (stimulating) versus high (inhibiting) concentrations of BMAL1/CLOCK, which correlate with different stages of sleep. Surprisingly, knock-out (KO) mice lacking key circadian genes (BMAL1, Cry, or Per), which were expected to have similar circadian dysfunction, exhibited distinct metabolic phenotypes. Although KO and chronic jet-lagged mice showed similar adipose tissue leptin dysregulation, striking differences were found in central leptin-mediated melanocortin signaling. Importantly, chronic jet-lagged mice had arrhythmic dampened pSTAT3 and POMC expression in arcuate nucleus neurons, despite high serum leptin concentrations. This was not rescued by exogenous leptin, indicating central leptin resistance.

The mechanism for the differential central effects of different circadian gene KOs has yet to be established. Nevertheless, the demonstration that chronic jet-lag in WT mice was sufficient to induce leptin resistance and a progressive gain in body fat and weight, independent of all previously identified obesity risk factors, implicates chronic circadian dysfunction as a contributing factor to the obesity epidemic.

N. M. Kettner et al., Circadian dysfunction induces leptin resistance in mice. Cell Metab. 10.1016/j.cmet.2015.06.005 (2015). [Abstract]

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