Dataset Information

Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis.

ABSTRACT: Neuregulin 4 (Nrg4) is an adipose tissue-enriched secreted factor that modulates glucose and lipid metabolism. Nrg4 is closely associated with obesity and preserves diet-induced metabolic disorders. However, the specific mechanisms via which Nrg4 regulates metabolic homeostasis remain incompletely understood. Here, this work finds that the Nrg4 receptor, ErbB4, is highly expressed in the hypothalamus, and the phosphorylation of hypothalamic ErbB4 is reduced in diet-induced obesity (DIO) mice. Peripheral Nrg4 can act on ErbB4 via blood circulation and excite neurons in the paraventricular nucleus of hypothalamus (PVN). Central administration of recombinant Nrg4 protein (rNrg4) reduces obesity and related metabolic disorders by influencing energy expenditure and intake. Overexpression of ErbB4 in the PVN protects against obesity, whereas its knock down in oxytocin (Oxt) neuron accelerates obesity. Furthermore, Nrg4-ErbB4 signaling excites Oxt release, and ablation of Oxt neuron considerably attenuates the effect of Nrg4 on energy balance. These data suggest that the hypothalamus is a key target of Nrg4, which partially explains the multifaceted roles of Nrg4 in metabolism.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC10238187 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis.

Zhang Yi Y Zhu Yangyang Y Wang Jinghui J Jin Li L Guo Mingwei M Chen Liwei L Zhang Lina L Li Yangyang Y Wan Baocheng B Zhang Rong R Jia Weiping W Hu Cheng C

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230414 16

Neuregulin 4 (Nrg4) is an adipose tissue-enriched secreted factor that modulates glucose and lipid metabolism. Nrg4 is closely associated with obesity and preserves diet-induced metabolic disorders. However, the specific mechanisms via which Nrg4 regulates metabolic homeostasis remain incompletely understood. Here, this work finds that the Nrg4 receptor, ErbB4, is highly expressed in the hypothalamus, and the phosphorylation of hypothalamic ErbB4 is reduced in diet-induced obesity (DIO) mice. Pe ...[more]

PMID: 37060105

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Project description:Neurons that synthesize melanin-concentrating hormone (MCH) colocalize GABA, regulate energy homeostasis, modulate water intake, and influence anxiety, stress, and social interaction. Similarly, vasopressin and oxytocin can influence the same behaviors and states, suggesting that these neuropeptides may exert part of their effect by modulating MCH neurons. Using whole cell recording in MCH-green fluorescent protein (GFP) transgenic mouse hypothalamic brain slices, we found that both vasopressin and oxytocin evoked a substantial excitatory effect. Both peptides reversibly increased spike frequency and depolarized the membrane potential in a concentration-dependent and tetrodotoxin-resistant manner, indicating a direct effect. Substitution of lithium for extracellular sodium, Na(+)/Ca(2+) exchanger blockers KB-R7943 and SN-6, and intracellular calcium chelator BAPTA, all substantially reduced the vasopressin-mediated depolarization, suggesting activation of the Na(+)/Ca(2+) exchanger. Vasopressin reduced input resistance, and the vasopressin-mediated depolarization was attenuated by SKF-96265, suggesting a second mechanism based on opening nonselective cation channels. Neither vasopressin nor oxytocin showed substantial excitatory actions on lateral hypothalamic inhibitory neurons identified in a glutamate decarboxylase 67 (GAD67)-GFP mouse. The primary vasopressin receptor was vasopressin receptor 1a (V1aR), as suggested by the excitation by V1aR agonist [Arg(8)]vasotocin, the selective V1aR agonist [Phe(2)]OVT and by the presence of V1aR mRNA in MCH cells, but not in other nearby GABA cells, as detected with single-cell RT-PCR. Oxytocin receptor mRNA was also detected in MCH neurons. Together, these data suggest that vasopressin or oxytocin exert a minimal effect on most GABA neurons in the lateral hypothalamus but exert a robust excitatory effect on presumptive GABA cells that contain MCH. Thus, some of the central actions of vasopressin and oxytocin may be mediated through MCH cells.

Dataset Information

Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis.

Publications

Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis.

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