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Angiotensin AT_1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity.

ABSTRACT: Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT_1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT_1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT_1A and Gαi, or stimulation via Ang-II type 2 (AT₂) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT_1A-inhibited AgRP neurons undergo a spontaneous G-protein "signal switch," whereby AT_1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT_1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT_1A-Gαi coupling within the AT_1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

SUBMITTER: Balapattabi K

PROVIDER: S-EPMC10530419 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Angiotensin AT1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity.

Balapattabi Kirthikaa K Yavuz Yavuz Y Jiang Jingwei J Deng Guorui G Mathieu Natalia M NM Ritter McKenzie L ML Opichka Megan A MA Reho John J JJ McCorvy John D JD Nakagawa Pablo P Morselli Lisa L LL Mouradian Gary C GC Atasoy Deniz D Cui Huxing H Hodges Matthew R MR Sigmund Curt D CD Grobe Justin L JL

Cell reports 20230802 8

Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via A ...[more]

PMID: 37540598

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Project description:Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain, with the highest expression in agouti-related peptide (AgRP) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that AgRP neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype-specific GHS-R knockout mouse (AgRP-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with one-quarter of food allotment given in the beginning of the light cycle and three-quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The CR-fed AgRP-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed AgRP-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these CR-fed AgRP-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP-Cre;Ghsrf/f mice revealed increased AgRP expression and a decreased expression of genes in β-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.

Dataset Information

Angiotensin AT_1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity.

Publications

Angiotensin AT<sub>1A</sub> receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity.

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