Modulation of Nhlh2 expression by energy availability leads to downstream effects on body weight regulation
Mice with a deletion of the hypothalamic basic helix-loop-helix transcription factor Nhlh2 (N2KO) display adult onset obesity, implicating Nhlh2 in the neuronal circuits regulating energy availability. Nhlh2 co-localizes with the hypothalamic thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus (PVN) and proopiomelanocortin (POMC) neurons in the arcuate nucleus. N2KO mice become obese due to reduced physical activity in the absence of hyperphagia making them a unique mouse model for the study weight gain, obesity and energy expenditure. Signals that regulate Nhlh2 and the effects of Nhlh2 on peripheral tissues remain largely unknown.
The research presented here utilized numerous techniques to investigate the effects of changes in energy availability on Nhlh2 expression. We show that Nhlh2 expression decreases significantly with food deprivation and cold exposure. Nhlh2 expression is stimulated with food return or leptin injection following food deprivation or return to room temperature following cold exposure. These data suggest that Nhlh2 gene expression responds positively to increased energy availability and negatively to reduced energy availability. These findings combined with the phenotype of N2KO mice led us to propose that Nhlh2 integrates energy availability inputs in various hypothalamic nuclei to drive expression of genes required for body weight maintenance.
Investigation into peripheral tissues in N2KO mice revealed that responses of genes in the hypothalamus-pituitary-thyroid axis, muscle, and brown and white adipose tissue to changes in energy availability require Nhlh2 expression. The responses of serum total T4 levels and UCP1 mRNA and UCP3 mRNA to energy availability signals are altered in N2KO mice. In addition, N2KO mice maintain body temperature with cold exposure but are unable to maintain body weight. In summary, my work provides new insight into the role of Nhlh2 in coordinating energy availability signals to downstream genes required for body weight maintenance and thermoregulation.
Anatomy & physiology;
0433: Anatomy & physiology