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Neuropeptide Y-Positive Neurons in the Dorsomedial Hypothalamus Are Involved in the Anorexic Effect of Angptl8.

ABSTRACT: Angiopoietin-like protein 8 (Angptl8), a recently identified member of the angiopoietin-like protein family (ANGPTLs), is a 22-kDa peptide synthesized in the liver. It participates in lipid metabolism by inhibiting lipoprotein lipase (LPL) activity, consequently increasing the triglyceride levels. Despite evidence that Angptl8 is involved in feeding control, the underlying mechanisms are unclear. Central and peripheral injections of Angptl8 significantly decreased food intake. Angptl8 was widely expressed in appetite-related nuclei, including the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), the ventromedial hypothalamus, and the arcuate nucleus (ARC) in the hypothalamus. Peripheral Angptl8 administration decreased c-Fos-positive neurons in the DMH. Central Angptl8 administration decreased c-Fos-positive neurons in the DMH and PVN but increased these neurons in the ARC. Angptl8 inhibited appetite via neuropeptide Y (NPY) neurons in the DMH. Furthermore, the chronic administration of Angptl8 decreased body weight gain and altered adipose tissue deposits. Nevertheless, neither peripheral nor central Angptl8 influenced the brown adipose tissue (BAT) morphology or uncoupling protein 1 (Ucp-1) expression in BAT. Taken together, these data suggested that Angptl8 modulates appetite and energy homeostasis.

SUBMITTER: Wang R

PROVIDER: S-EPMC6305345 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:ObjectiveCentral cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake.MethodsTo selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete the Chat gene exclusively in the DMH, we injected an AAV carrying a Cre recombinase transgene into the DMH of floxed ChAT mice. Food intake was measured with and without selective stimulation of DMH cholinergic neurons.ResultsMice lacking the Chat gene in the DMH show reduced body weight as compared to control. Chemogenetic activation of DMH cholinergic neurons promotes food intake. This orexigenic effect is further supported by experiments of optogenetic stimulation of DMH cholinergic neurons. DMH cholinergic neurons innervate pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Treatment with acetylcholine (ACh) enhances GABAergic inhibitory transmission to ARC POMC neurons that is blocked by the muscarinic receptor antagonist. Direct activation of cholinergic fibers in the ARC readily stimulates food intake that is also abolished by the muscarinic receptor antagonist.ConclusionACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMHACh → ARCPOMC pathway plays an important role in the control of food intake and body weight.

Project description:ObjectiveBrown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa).MethodsIn order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses.ResultsA subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor γ coactivator 1 α (Pgc1α) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1 nor Pgc1α mRNA expression.ConclusionDMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMH(ACh)-Rpa(5-HT) pathway may mediate physiological heat-defense responses to elevated environmental temperature.

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Neuropeptide Y-Positive Neurons in the Dorsomedial Hypothalamus Are Involved in the Anorexic Effect of Angptl8.

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