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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

Intra-DMH/DHA leptin injections correct hypothermia in leptin-deficient ob/ob mice. A. Schematic drawing of bilateral cannulations of the DMH/DHA area. B. Example of the anatomical verification of correctly cannulated DMH/DHA. C. Rectal body temperature of vehicle treated wildtype mice (n = 8), vehicle treated ob/ob mice (n = 5), leptin treated wildtype mice (n = 8), and leptin treated ob/ob mice (n = 6) after three consecutive days of treatment. *ppost-hoc < 0.02. D. Body weight change after three consecutive days of vehicle or leptin treatment. †pt-test < 0.07. E. 24 h food intake during three days of vehicle injections and during three days of leptin injections. wt, wildtype.
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fig5: Intra-DMH/DHA leptin injections correct hypothermia in leptin-deficient ob/ob mice. A. Schematic drawing of bilateral cannulations of the DMH/DHA area. B. Example of the anatomical verification of correctly cannulated DMH/DHA. C. Rectal body temperature of vehicle treated wildtype mice (n = 8), vehicle treated ob/ob mice (n = 5), leptin treated wildtype mice (n = 8), and leptin treated ob/ob mice (n = 6) after three consecutive days of treatment. *ppost-hoc < 0.02. D. Body weight change after three consecutive days of vehicle or leptin treatment. †pt-test < 0.07. E. 24 h food intake during three days of vehicle injections and during three days of leptin injections. wt, wildtype.

Mentions: To test the physiological relevance of DMH/DHA LepRb neurons in leptin-stimulated thermogenesis, we injected leptin or vehicle into the DMH/DHA of leptin-deficient ob/ob mice and control littermates twice daily over three days. Correct cannula placement was verified anatomically after the experiment (Figure 5B). As expected, all ob/ob mice were hypothermic and obese before leptin treatment compared to their control littermates (p < 0.0002, data not shown). Leptin treatment had no measureable effect on body temperature in wildtype littermates at the end of the three day treatment, while intra-DMH/DHA leptin injection in ob/ob mice normalized hypothermia to body temperatures comparable to control littermates (Figure 5C). Leptin also significantly elevated body temperature in ob/ob mice compared to vehicle treated ob/ob mice (p < 0.02; Figure 5C). Leptin treatment also trended towards suppressing body weight gain in ob/ob mice compared to vehicle treated ob/ob mice, even though data did not reach statistical significance (p < 0.07; Figure 5D). In line with our previous observations in Figure 4F, activation of LepRb neurons via intra-DMH/DHA leptin administration did not affect food intake (Figure 5E).


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)

Intra-DMH/DHA leptin injections correct hypothermia in leptin-deficient ob/ob mice. A. Schematic drawing of bilateral cannulations of the DMH/DHA area. B. Example of the anatomical verification of correctly cannulated DMH/DHA. C. Rectal body temperature of vehicle treated wildtype mice (n = 8), vehicle treated ob/ob mice (n = 5), leptin treated wildtype mice (n = 8), and leptin treated ob/ob mice (n = 6) after three consecutive days of treatment. *ppost-hoc < 0.02. D. Body weight change after three consecutive days of vehicle or leptin treatment. †pt-test < 0.07. E. 24 h food intake during three days of vehicle injections and during three days of leptin injections. wt, wildtype.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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fig5: Intra-DMH/DHA leptin injections correct hypothermia in leptin-deficient ob/ob mice. A. Schematic drawing of bilateral cannulations of the DMH/DHA area. B. Example of the anatomical verification of correctly cannulated DMH/DHA. C. Rectal body temperature of vehicle treated wildtype mice (n = 8), vehicle treated ob/ob mice (n = 5), leptin treated wildtype mice (n = 8), and leptin treated ob/ob mice (n = 6) after three consecutive days of treatment. *ppost-hoc < 0.02. D. Body weight change after three consecutive days of vehicle or leptin treatment. †pt-test < 0.07. E. 24 h food intake during three days of vehicle injections and during three days of leptin injections. wt, wildtype.
Mentions: To test the physiological relevance of DMH/DHA LepRb neurons in leptin-stimulated thermogenesis, we injected leptin or vehicle into the DMH/DHA of leptin-deficient ob/ob mice and control littermates twice daily over three days. Correct cannula placement was verified anatomically after the experiment (Figure 5B). As expected, all ob/ob mice were hypothermic and obese before leptin treatment compared to their control littermates (p < 0.0002, data not shown). Leptin treatment had no measureable effect on body temperature in wildtype littermates at the end of the three day treatment, while intra-DMH/DHA leptin injection in ob/ob mice normalized hypothermia to body temperatures comparable to control littermates (Figure 5C). Leptin also significantly elevated body temperature in ob/ob mice compared to vehicle treated ob/ob mice (p < 0.02; Figure 5C). Leptin treatment also trended towards suppressing body weight gain in ob/ob mice compared to vehicle treated ob/ob mice, even though data did not reach statistical significance (p < 0.07; Figure 5D). In line with our previous observations in Figure 4F, activation of LepRb neurons via intra-DMH/DHA leptin administration did not affect food intake (Figure 5E).

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