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

Rezai-Zadeh K, Yu S, Jiang Y, Laque A, Schwartzenburg C, Morrison CD, Derbenev AV, Zsombok A, Münzberg H - Mol Metab (2014)

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

View Article: PubMed Central - PubMed

Affiliation: Central Leptin Signaling, Pennington Biomedical Research Center (PBRC), LSU System, Baton Rouge, LA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

DMH/DHA LepRb neurons are activated by leptin. A. Representative images of LepRbGFP reporter mice three hours after acute i.p. vehicle (left panel, n = 3) or leptin (5 mg/kg body weight, right panel, n = 4) treatment. Sections were stained for cFos as a surrogate for neuronal activation and GFP as a surrogate for LepRb neurons. B. Percentage of LepRbGFP neurons that are co-localized with cFos within the DMH/DHA. **pt-test < 0.01. C. Total number of LepRbGFP neurons in the DMH/DHA.
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fig1: DMH/DHA LepRb neurons are activated by leptin. A. Representative images of LepRbGFP reporter mice three hours after acute i.p. vehicle (left panel, n = 3) or leptin (5 mg/kg body weight, right panel, n = 4) treatment. Sections were stained for cFos as a surrogate for neuronal activation and GFP as a surrogate for LepRb neurons. B. Percentage of LepRbGFP neurons that are co-localized with cFos within the DMH/DHA. **pt-test < 0.01. C. Total number of LepRbGFP neurons in the DMH/DHA.

Mentions: Cold and pyrogen-stimulated BAT thermogenesis both work through the indirect activation of DMH/DHA neurons [17,28,29], and we have previously shown that acute cold-exposure activates DMH/DHA LepRb neurons [18]. To test if thermogenic leptin action occurs through a similar mechanism, we examined neuronal activation in DMH/DHA LepRb neurons in LepRbGFP reporter mice following i.p. injection of leptin or vehicle. Neuronal activation was evaluated by quantifying the induction of cFos (a surrogate for neuronal activation) in DMH/DHA LepRbGFP neurons. Leptin increased cFos two-fold in DMH/DHA LepRb neurons compared to vehicle treated mice (p < 0.01, n = 3–4, Figure 1A–C), indicating that leptin activates DMH/DHA LepRb neurons similar to acute cold exposure [18]. This further supports the hypothesis that leptin directly acts on DMH/DHA LepRb neurons to elevate energy expenditure and contributes to weight loss.


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

Rezai-Zadeh K, Yu S, Jiang Y, Laque A, Schwartzenburg C, Morrison CD, Derbenev AV, Zsombok A, Münzberg H - Mol Metab (2014)

DMH/DHA LepRb neurons are activated by leptin. A. Representative images of LepRbGFP reporter mice three hours after acute i.p. vehicle (left panel, n = 3) or leptin (5 mg/kg body weight, right panel, n = 4) treatment. Sections were stained for cFos as a surrogate for neuronal activation and GFP as a surrogate for LepRb neurons. B. Percentage of LepRbGFP neurons that are co-localized with cFos within the DMH/DHA. **pt-test < 0.01. C. Total number of LepRbGFP neurons in the DMH/DHA.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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fig1: DMH/DHA LepRb neurons are activated by leptin. A. Representative images of LepRbGFP reporter mice three hours after acute i.p. vehicle (left panel, n = 3) or leptin (5 mg/kg body weight, right panel, n = 4) treatment. Sections were stained for cFos as a surrogate for neuronal activation and GFP as a surrogate for LepRb neurons. B. Percentage of LepRbGFP neurons that are co-localized with cFos within the DMH/DHA. **pt-test < 0.01. C. Total number of LepRbGFP neurons in the DMH/DHA.
Mentions: Cold and pyrogen-stimulated BAT thermogenesis both work through the indirect activation of DMH/DHA neurons [17,28,29], and we have previously shown that acute cold-exposure activates DMH/DHA LepRb neurons [18]. To test if thermogenic leptin action occurs through a similar mechanism, we examined neuronal activation in DMH/DHA LepRb neurons in LepRbGFP reporter mice following i.p. injection of leptin or vehicle. Neuronal activation was evaluated by quantifying the induction of cFos (a surrogate for neuronal activation) in DMH/DHA LepRbGFP neurons. Leptin increased cFos two-fold in DMH/DHA LepRb neurons compared to vehicle treated mice (p < 0.01, n = 3–4, Figure 1A–C), indicating that leptin activates DMH/DHA LepRb neurons similar to acute cold exposure [18]. This further supports the hypothesis that leptin directly acts on DMH/DHA LepRb neurons to elevate energy expenditure and contributes to weight loss.

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

View Article: PubMed Central - PubMed

Affiliation: Central Leptin Signaling, Pennington Biomedical Research Center (PBRC), LSU System, Baton Rouge, LA, USA.

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.

No MeSH data available.


Related in: MedlinePlus