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

Dec 19, 2014Endocrinology

Leptin helps reset the internal clock in male obese mice by indirectly affecting the brain's light-sensitive timing center

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Abstract

Ob/ob mice showed altered photic synchronization, including augmented light-induced phase delays.

Leptin is associated with changes in circadian timing in the context of obesity.
Acute treatment with leptin normalized photic responses in the suprachiasmatic nucleus (SCN) at both behavioral and molecular levels.
Light exposure modulated leptin-induced signaling in the arcuate nucleus and hypothalamic nuclei, suggesting a complex interaction.
The expression of phosphorylated signal transducer and activator of transcription 3 (P-STAT3) in the SCN did not depend on leptin presence.
Findings indicate that leptin may influence the SCN indirectly through pathways involving the medial hypothalamus.

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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.

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

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