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Hypothalamic dopamine signaling regulates brown fat thermogenesis

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The dopamine system is widely known to modulate the brain reward system, affecting feeding behavior. The hypothalamus has been largely studied in the regulation of energy metabolism in peripheral tissues. Since dopamine receptors are expressed in the hypothalamus, we investigated the potential metabolic actions of the hypothalamic dopamine system. We found that the pharmacological or chemogenetic stimulation of the dopamine receptor 2 (D2R) in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system to exert its actions. The activation of D2R requires the orexin system, since D2R fails to induce thermogenesis in orexin-deficient mice or when orexin receptor 1 is blocked. D2R stimulation and orexin inhibit protein kinase A (PKA) activity and the specific inhibition of PKA in the LHA/ZI recapitulated the thermogenic effects of D2R stimulation and orexin. In line with these preclinical findings, patients undergoing treatment with the D2R agonist cabergoline experienced an increase in energy expenditure that was evident as early as 3 months and persisted after one year, leading to total body weight and fat loss. Taking into account that D2R agonists are clinically relevant, our results may help to understand how these compounds act in the CNS to regulate energy balance.



Adipose Tissue, Brown, Animals, Bromocriptine, Dopamine, Female, Humans, Hypothalamus, Injections, Intraventricular, Male, Rats, Signal Transduction, Thermogenesis

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Nature Metabolism

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