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Circadian Dysfunction Induces Leptin Resistance in Mice.

Nicole M Kettner1, Sara A Mayo2, Jack Hua2

  • 1Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

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Circadian disruption links to obesity by affecting body weight control. This study reveals how genetic and environmental factors disrupt energy balance and Leptin signaling, highlighting Leptin resistance in circadian dysfunction-induced obesity.

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Area of Science:

  • Chronobiology
  • Metabolic Syndrome
  • Endocrinology

Background:

  • Circadian disruption is linked to obesity, suggesting the central clock's role in body weight regulation.
  • Leptin signaling is crucial for energy homeostasis and appetite control.

Purpose of the Study:

  • To investigate how genetic mutations and chronic jet lag affect energy homeostasis and Leptin signaling.
  • To elucidate the role of the BMAL1/CLOCK complex in regulating leptin transcription in adipose tissue.
  • To understand the interplay between central and peripheral circadian clocks in Leptin endocrine feedback.

Main Methods:

  • Comprehensive screening of wild-type and three circadian mutant mouse models.
  • Exposure to chronic jet lag to simulate circadian disruption.
  • Analysis of energy homeostasis, body weight, body composition, and Leptin signaling pathways.
  • Investigation of POMC neuron deregulation in the arcuate nucleus.

Main Results:

  • Distinct genetic and physiological interventions differentially disrupt energy homeostasis and Leptin signaling.
  • BMAL1/CLOCK generates the circadian rhythm of C/EBPα-mediated leptin transcription in adipose tissue.
  • Per and Cry mutant mice exhibit disrupted peripheral clocks and deregulated leptin but show opposite body weight phenotypes.
  • Chronic jet lag disrupts the adipose clock and induces central Leptin resistance in wild-type mice.
  • Coupling of central and peripheral clocks is essential for Leptin endocrine feedback homeostasis.

Conclusions:

  • Circadian dysfunction, particularly through Leptin resistance, plays a key role in obesity and metabolic syndromes.
  • The study highlights the intricate connection between the central and peripheral clocks in maintaining metabolic health.
  • Understanding these mechanisms could lead to novel therapeutic strategies for obesity and related metabolic disorders.