Leptin Normalizes Photic Synchronization in Male ob/ob Mice, via Indirect Effects on the Suprachiasmatic Nucleus

Abstract

Mounting evidence indicates a strong link between metabolic diseases and circadian dysfunctions. The metabolic hormone leptin, substantially increased in dietary obesity, displays chronobiotic properties. Here we investigated whether leptin is involved in the alteration of timing associated with obesity, via direct or indirect effects on the suprachiasmatic nucleus (SCN), the site of the master clock. Photic synchronization was studied in obese ob/ob mice (deficient in leptin), either injected or not with high doses of recombinant murine leptin (5 mg/kg). This was performed first at a behavioral level, by shifting the light-dark cycle and inducing phase shifts by 30-minute light pulses and then at molecular levels (c-FOS and P-ERK1/2). Moreover, to characterize the targets mediating the chronomodulatory effects of leptin, we studied the induction of phosphorylated signal transducer and activator of transcription 3 (P-STAT3) in the SCN and in different structures projecting to the SCN, including the medial hypothalamus. Ob/ob mice showed altered photic synchronization, including augmented light-induced phase delays. Acute leptin treatment normalized the photic responses of the SCN at both the behavioral and molecular levels (decrease of light-induced c-FOS). Leptin-induced P-STAT3 was modulated by light in the arcuate nucleus and both the ventromedial and dorsomedial hypothalamic nuclei, whereas its expression was independent of the presence of leptin in the SCN. These results suggest an indirect action of leptin on the SCN, possibly mediated by the medial hypothalamus. Taken together, these results highlight a central role of leptin in the relationship between metabolic disturbances and circadian disruptions.

Endocrine regulation of circadian physiology

“…Ob/ob mice (carrying a lossof-function mutation of the Lep gene) show altered photic responses of the circadian clock at both behavioral and molecular levels, which can be normalized by timed injections of leptin. In the same study, however, the authors found that systemic leptin injections failed to stimulate canonical leptin signaling cascades in the SCN, suggesting an indirect mechanism for leptin's circadian resetting effects (Grosbellet et al 2015b). Db/db mice (expressing a nonfunctional version of the long isoform of leptin receptor gene, Obrb) show severely disrupted loco motor activity and feeding rhythms together with exaggerated molecular photic responses in the SCN (Grosbellet et al 2015a).…”

White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies

“…Genetically obese and diabetic db/db mice, lacking Ob-Rb, are arrhythmic regarding feeding and general activity; they present an extended endogenous period and altered photic integration [76] . The same group has demonstrated that LEP modulates daily blood glucose rhythmicity by modulating food intake [77,78] . Additionally, rats submitted to forced activity during the sleeping phase, showed altered temporal pattern of food intake, loss of glucose rhythmicity and a reversed rhythm of triacylglycerol levels, though CNS activity was intact.…”

Circadian phenotyping of obese and diabetic db/db mice

“…For example, diet-induced obesity in rodents lengthens the endogenous period of wheel-running behavior and body temperature under constant darkness, and reduces photic resetting of the master clock, as shown by smaller light-induced phase-advances and slower rate of re-entrainment after a jet-lag (phase-advance) [11,12]. Genetically obese ob/ob mice, lacking functional leptin, display no change in the endogenous period, but display altered photic resetting, as shown by larger light-induced phase-delays and faster rate of re-entrainment after a delayed lightedark cycle [14,15], and disturbances of peripheral clocks [16]. Moreover, insulino-dependent diabetes, induced in rodents by the chemical destruction of b-pancreatic cells, leads to circadian disturbances in peripheral clocks [17,18] and alterations of photic resetting of the master clock [19,20].…”