Elsevier

Molecular Metabolism

Volume 3, Issue 7, October 2014, Pages 681-693
Molecular Metabolism

Original article
Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake

https://doi.org/10.1016/j.molmet.2014.07.008Get rights and content
Under a Creative Commons license
open access

Abstract

Objective

Leptin responsive neurons play an important role in energy homeostasis, controlling specific autonomic, behavioral, and neuroendocrine functions. We have previously identified a population of leptin receptor (LepRb) expressing neurons within the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) which are related to neuronal circuits that control brown adipose tissue (BAT) thermogenesis. Intra-DMH leptin injections also activate sympathetic outflow to BAT, but whether such effects are mediated directly via DMH/DHA LepRb neurons and whether this is physiologically relevant for whole body energy expenditure and body weight regulation has yet to be determined.

Methods

We used pharmacosynthetic receptors (DREADDs) to selectively activate DMH/DHA LepRb neurons. We further deleted LepRb with virally driven cre-recombinase from DMH/DHA neurons and determined the physiological importance of DMH/DHA LepRb neurons in whole body energy homeostasis.

Results

Neuronal activation of DMH/DHA LepRb neurons with DREADDs promoted BAT thermogenesis and locomotor activity, which robustly induced energy expenditure (p < 0.001) and decreases body weight (p < 0.001). Similarly, intra-DMH/DHA leptin injections normalized hypothermia and attenuated body weight gain in leptin-deficient ob/ob mice. Conversely, ablation of LepRb from DMH/DHA neurons remarkably drives weight gain (p < 0.001) by reducing energy expenditure (p < 0.001) and locomotor activity (p < 0.001). The observed changes in body weight were largely independent of food intake.

Conclusion

Taken together, our data highlight that DMH/DHA LepRb neurons are sufficient and necessary to regulate energy expenditure and body weight.

Keywords

Leptin
Thermoregulation
Energy expenditure
Dorsomedial hypothalamus
DREADD

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