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Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.

ABSTRACT: The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic signatures of cell types and their links to function remain poorly understood. Using single-nucleus RNA sequencing, we describe nine CeA cell clusters, of which four are mostly associated with appetitive and two with aversive behaviors. To analyze the activation mechanism of appetitive CeA neurons, we characterized serotonin receptor 2a (Htr2a)-expressing neurons (CeA^Htr2a) that comprise three appetitive clusters and were previously shown to promote feeding. In vivo calcium imaging revealed that CeA^Htr2a neurons are activated by fasting, the hormone ghrelin, and the presence of food. Moreover, these neurons are required for the orexigenic effects of ghrelin. Appetitive CeA neurons responsive to fasting and ghrelin project to the parabrachial nucleus (PBN) causing inhibition of target PBN neurons. These results illustrate how the transcriptomic diversification of CeA neurons relates to fasting and hormone-regulated feeding behavior.

SUBMITTER: Peters C

PROVIDER: S-EPMC10208581 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.

Peters Christian C He Songwei S Fermani Federica F Lim Hansol H Ding Wenyu W Mayer Christian C Klein Rüdiger R

Science advances 20230524 21

The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic signatures of cell types and their links to function remain poorly understood. Using single-nucleus RNA sequencing, we describe nine CeA cell clusters, of which four are mostly associated with appetitive and two with aversive behaviors. To analyze the activation mechanism of appetitive CeA neurons, we characterized serotonin rece ...[more]

PMID: 37224253

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Project description:ObjectiveGhrelin is a stomach-derived hormone that affects food intake and regulates blood glucose. The best-characterized actions of ghrelin are mediated by its binding to and activation of the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Adequate examination of the identity, function, and relevance of specific subsets of GHSR-expressing neurons has been hampered by the absence of a suitable Cre recombinase (Cre)-expressing mouse line with which to manipulate gene expression in a targeted fashion within GHSR-expressing neurons. The present study aims to characterize the functional significance and neurocircuitry of GHSR-expressing neurons in the mediobasal hypothalamus (MBH), as they relate to ghrelin-induced food intake and fasting-associated rebound hyperphagia, using a novel mouse line in which Cre expression is controlled by the Ghsr promoter.MethodsA Ghsr-IRES-Cre mouse line that expresses Cre directed by the Ghsr promoter was generated. The line was validated by comparing Cre activity in reporter mice to the known brain distribution pattern of GHSR. Next, the requirement of MBH GHSR-expressing neuronal activity in mediating food intake in response to administered ghrelin and in response to fasting was assessed after stereotaxic delivery of inhibitory designer receptor exclusively activated by designer drugs (DREADD) virus to the MBH. In a separate cohort of Ghsr-IRES-Cre mice, stereotaxic delivery of stimulatory DREADD virus to the MBH was performed to assess the sufficiency of MBH GHSR-expressing neuronal activity on food intake. Finally, the distribution of MBH GHSR-expressing neuronal axonal projections was assessed in the DREADD virus-injected animals.ResultsThe pattern of Cre activity in the Ghsr-IRES-Cre mouse line mostly faithfully reproduced the known GHSR expression pattern. DREADD-assisted inhibition of MBH GHSR neuronal activity robustly suppressed the normal orexigenic response to ghrelin and fasting-associated rebound food intake. DREADD-assisted stimulation of MBH GHSR neuronal activity was sufficient to induce food intake. Axonal projections of GHSR-expressing MBH neurons were observed in a subset of hypothalamic and extra-hypothalamic regions.ConclusionsThese results suggest that 1) activation of GHSR-expressing neurons in the MBH is required for the normal feeding responses following both peripheral administration of ghrelin and fasting, 2) activation of MBH GHSR-expressing neurons is sufficient to induce feeding, and 3) axonal projections to a subset of hypothalamic and/or extra-hypothalamic regions likely mediate these responses. The Ghsr-IRES-Cre line should serve as a valuable tool to further our understanding of the functional significance of ghrelin-responsive/GHSR-expressing neurons and the neuronal circuitry within which they act.

Project description:RDH1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here, we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. Glucose intolerance and insulin resistance develop following increased adiposity. Despite the increase in white fat pads, epididymal white adipose does not express Rdh1, nor does muscle. Brown adipose tissue (BAT) and liver express Rdh1 at relatively high levels compared to other tissues. Rdh1 ablation lowered body temperatures during ambient conditions. Given the decreased body temperature, we focused on BAT. A lack of differences in BAT adipogenic gene expression between Rdh1-null mice and wild-type mice, including Pparg, Prdm16, Zfp516 and Zfp521, indicated that the phenotype was not driven by brown adipose hyperplasia. Rather, Rdh1 ablation eliminated the increase in BAT atRA that occurs after re-feeding. This disruption of atRA homeostasis increased fatty acid uptake, but attenuated lipolysis in primary brown adipocytes, resulting in increased lipid content and larger lipid droplets. Rdh1 ablation also decreased mitochondrial proteins, including CYCS and UCP1, the mitochondria oxygen consumption rate, and disrupted the mitochondria membrane potential, further reflecting impaired BAT function, resulting in both BAT and white adipose hypertrophy. RNAseq revealed dysregulation of 424 BAT genes in null mice, which segregated predominantly into differences after fasting vs after re-feeding. Exceptions were Rbp4 and Gbp2b, which increased during both dietary conditions. Rbp4 encodes the serum retinol-binding protein-an insulin desensitizer. Gbp2b encodes a GTPase. Because Gbp2b increased several hundred-fold, we overexpressed it in brown adipocytes. This caused a shift to larger lipid droplets, suggesting that GBP2b affects signaling downstream of the ?-adrenergic receptor during basal thermogenesis. Thus, Rdh1-generated atRA in BAT regulates multiple genes that promote BAT adaptation to whole-body energy status, such as fasting and re-feeding. These gene expression changes promote optimum mitochondria function and thermogenesis, limiting adiposity. Attenuation of adiposity and insulin resistance suggests that RDH1 mitigates metabolic syndrome.

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Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.

Publications

Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.

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