Journal of Applied Physiology

Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding

Hung Hsuchou, Yuping Wang, Germaine G. Cornelissen-Guillaume, Abba J. Kastin, Eugjin Jang, Franz Halberg, Weihong Pan


Leptin, a hormone mainly produced by fat cells, shows cell-specific effects to regulate feeding and metabolic activities. We propose that an important feature of metabolic dysregulation resulting in obesity is the loss of the circadian rhythm of biopotentials. This was tested in the pan-leptin receptor knockout (POKO) mice newly generated in our laboratory. In the POKO mice, leptin no longer induced pSTAT-3 signaling after intracerebroventricular injection. Three basic phenotypes were observed: the heterozygotes had similar weight and adiposity as the wildtype (WT) mice (more than 60% of the mice); the homozygotes were either fatter (about 30%), or rarely leaner (less than 5%) than the WT mice. By early adulthood, the POKO mice had higher average body weight and adiposity than their respective same sex WT littermate controls, and this was consistent among different batches. The homozygote fat POKO showed significant reduction of midline estimating statistic of rhythm of circadian parameters, and shifts of ultradian rhythms. The blunted circadian rhythm of these extremely obese POKO mice was also seen in their physical inactivity, longer feeding bouts, and higher food intake. The extent of obesity correlated with the blunted circadian amplitude, accumulative metabolic and locomotor activities, and the severity of hyperphagia. This contrasts with the heterozygote POKO mice which showed little obesity and metabolic disturbance, and only subtle changes of the circadian rhythm of metabolic activity without alterations in feeding behavior. The results provide a novel aspect of leptin resistance, almost manifesting as an "all or none" phenomenon.

  • Leptin
  • Circadian rhythm
  • Metabolic activity
  • Obesity
  • Physical inactivity