Leptin Receptor Signaling in Sim1-Expressing Neurons Regulates Body Temperature and Adaptive Thermogenesis

Area of Science:

• Neuroscience
• Metabolic Regulation
• Endocrinology

Background:

• Leptin receptor B (LepRb) signaling is vital for energy homeostasis, but its role in obesity pathophysiology is unclear.
• The paraventricular nucleus (PVN) of the hypothalamus regulates energy balance, and LepRb's function within PVN neurons is debated.
• Sim1-Cre mice are a valuable model for studying PVN function due to Sim1 gene expression patterns.

Purpose of the Study:

• To investigate the physiological role of LepRb in Sim1-expressing neurons.
• To elucidate the contribution of LepRb signaling in Sim1 neurons to body weight regulation and energy expenditure.
• To examine the impact of LepRb deficiency in Sim1 neurons on thermoregulation and adaptive thermogenesis.

Main Methods:

• Utilized LepRb-floxed × Sim1-Cre mice to create Sim1-specific LepRb-deficient models.
• Assessed body weight, food intake, energy expenditure, and body temperature in response to diet and ambient temperature.
• Evaluated cold-induced adaptive thermogenesis, uncoupling protein 1 (UCP1) expression in brown adipose tissue, and serum thyroxine (T4) levels.

Main Results:

• Sim1-specific LepRb deficiency led to hypophagia on regular chow but increased weight gain on a high-fat diet.
• Deletion of LepRb in Sim1 neurons decreased body temperature and energy expenditure.
• Homozygous knockout mice exhibited disrupted cold-induced adaptive thermogenesis, impaired UCP1 upregulation, and reduced serum T4.

Conclusions:

• LepRb signaling within Sim1 neurons plays a critical role in regulating body weight.
• LepRb signaling in Sim1 neurons is essential for maintaining core body temperature and energy expenditure.
• Defective LepRb signaling in Sim1 neurons impairs thermoregulatory responses to cold, contributing to metabolic dysfunction.