Removing melatonin receptor type 1 signaling leads to selective leptin resistance in the arcuate nucleus

Recent studies have highlighted the involvement of melatonin in the regulation of energy homeostasis. In this study, we report that mice lacking melatonin receptor 1 (MT₁ KO) gained more weight, had a higher cumulative food intake, and were more hyperphagic after fasting compared to controls (WT). In response to a leptin injection, MT₁ KO mice showed a diminished reduction in body weight and food intake. To evaluate hypothalamic leptin signaling, we tested leptin-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Leptin failed to induce STAT3 phosphorylation in MT₁ KO mice beyond levels observed in mice injected with phosphate-buffered saline (PBS). Furthermore, STAT3 phosphorylation within the arcuate nucleus (ARH) was decreased in MT₁ KO mice. Leptin receptor mRNA levels in the hypothalamus of MT₁ KO were significantly reduced (about 50%) compared to WT. This study shows that: (a) MT₁ deficiency causes weight gain and increased food intake; (b) a lack of MT₁ signaling induces leptin resistance; (c) leptin resistance is ARH region-specific; and (d) leptin resistance is likely due to down-regulation of the leptin receptor. Our data demonstrate that MT₁ signaling is an important modulator of leptin signaling.