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

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.

• Authors: Kavon Rezai-Zadeh, Sanghou Yu, Yanyan Jiang, Amanda Laque, Candice Schwartzenburg, Christopher D Morrison, Andrei V Derbenev, Andrea Zsombok, Heike Münzberg
• Journal: Molecular metabolism (Mol Metab) Vol. 3 Issue 7 Pg. 681-93 (Oct 2014) ISSN: 2212-8778 [Print] Germany
• PMID: 25352997 (Publication Type: Journal Article)