Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

TLDR

Leptin resistance in diet‑induced obese mice is marked by high serum leptin and a blunted response, yet the central nervous system defects responsible are unknown, and region‑specific resistance—particularly in the arcuate nucleus—has not been characterized but may drive obesity. The study aimed to uncover mechanisms of leptin‑resistant STAT3 activation in the arcuate nucleus by measuring mRNA of key signaling molecules in the leptin receptor‑STAT3 pathway. Researchers mapped leptin‑responsive cells using phospho‑STAT3 immunohistochemistry and quantified mRNA expression of pathway components in the arcuate nucleus of high‑fat‑diet mice. They found that leptin‑induced P‑STAT3 signaling is markedly reduced in the arcuate nucleus as early as six days of high‑fat feeding, while other nuclei remain responsive, and that suppressor of cytokine signaling‑3 is specifically upregulated there, indicating selective leptin resistance driven by SOCS‑3.

Abstract

Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.