Dataset Information

Ciliary Type III Adenylyl Cyclase in the VMH Is Crucial for High-Fat Diet-Induced Obesity Mediated by Autophagy.

ABSTRACT: Neuronal primary cilia are crucial for body weight maintenance. Type III adenylyl cyclase (AC3) is abundantly enriched in neuronal cilia, and mice with global AC3 ablation are obese. However, whether AC3 regulates body weight through its ciliary expression and the mechanism underlying this potential regulation are not clear. In this study, humanized AC3 knock-in mice that are resistant to high-fat diet (HFD)-induced obesity are generated, and increases in the number and length of cilia in the ventromedial hypothalamus (VMH) are shown. It is demonstrated that mice with specifically knocked down ciliary AC3 expression in the VMH show pronounced HFD-induced obesity. In addition, in vitro and in vivo analyses of the VMH show that ciliary AC3 regulates autophagy by binding an autophagy-related gene, gamma-aminobutyric acid A receptor-associated protein (GABARAP). Mice with GABARAP knockdown in the VMH exhibit exacerbated HFD-induced obesity. Overall, the findings may reveal a potential mechanism by which ciliary AC3 expression regulates body weight in the mouse VMH.

SUBMITTER: Yang D

PROVIDER: S-EPMC8787410 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Ciliary Type III Adenylyl Cyclase in the VMH Is Crucial for High-Fat Diet-Induced Obesity Mediated by Autophagy.

Yang Dong D Wu Xiangbo X Wang Weina W Zhou Yanfen Y Wang Zhenshan Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20211116 3

Neuronal primary cilia are crucial for body weight maintenance. Type III adenylyl cyclase (AC3) is abundantly enriched in neuronal cilia, and mice with global AC3 ablation are obese. However, whether AC3 regulates body weight through its ciliary expression and the mechanism underlying this potential regulation are not clear. In this study, humanized AC3 knock-in mice that are resistant to high-fat diet (HFD)-induced obesity are generated, and increases in the number and length of cilia in the ve ...[more]

PMID: 34783461

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Project description:ObjectiveObesity-associated metabolic dysfunction is a major public health concern worldwide. Endothelial dysfunction is a hallmark of metabolic dysfunction, and endothelial cells affect metabolic functions. Because autophagy-related gene 7 (ATG7) is involved in various cellular physiology, we investigated the roles of endothelial cell-ATG7 (EC-ATG7) on high-fat diet-induced obesity and its related metabolic dysfunction.MethodsWe generated an endothelial-specific Atg7 knock-out mouse by breeding Atg7flox/flox mouse with the Chd5-Cre mouse, and investigated the metabolic phenotypes associated with high-fat diet (HFD)-induced obesity. Body weight, food intake, glucose tolerance, insulin sensitivity, and liver fat accumulation were measured in endothelial Atg7 deficient (Atg7ΔEnd) and control mice (Atg7f/f). Adipose tissue inflammation was assessed by measuring the expression of pro-inflammatory genes. Furthermore, we performed indirect calorimetry and examined the insulin signaling pathway molecules.ResultsWe found that deletion of EC-Atg7 ameliorated HFD-induced weight gain, fatty liver, and adipocyte hypertrophy and inflammatory response in adipose tissue, and improved insulin sensitivity without changing glucose tolerance. These metabolic effects seem to be due to the reduced food intake because there were no differences in energy expenditure, energy excretion to feces, and physical activity. Interestingly, the deletion of EC-Atg7 protected from HFD-induced vascular rarefaction, and the knock-down of Atg7 in endothelial cells protected from fatty acid-induced cell death.ConclusionsOur results suggest that EC-Atg7 deletion ameliorates HFD-induced obesity and its related metabolic dysfunction, such as insulin resistance and fatty liver by attenuating appetite and vascular rarefaction. The EC-Atg7 deletion may protect the endothelial cells from lipotoxicity and impaired angiogenesis, which preserves the endothelial function in metabolic tissues. These findings may have implications for developing new therapeutic strategies for preventing and treating obesity and its associated health risks.

Project description:Type III adenylyl cyclase (AC3, ADCY3) is predominantly enriched in neuronal primary cilia throughout the central nervous system (CNS). Genome-wide association studies in humans have associated ADCY3 with major depressive disorder and autistic spectrum disorder, both of which exhibit sexual dimorphism. To date, it is unclear how AC3 affects protein phosphorylation and signal networks in central neurons, and what causes the sexual dimorphism of autism. We employed a mass spectrometry (MS)-based phosphoproteomic approach to quantitatively profile differences in phosphorylation between inducible AC3 knockout (KO) and wild type (WT), male and female mice. In total, we identified 4,655 phosphopeptides from 1,756 proteins, among which 565 phosphopeptides from 322 proteins were repetitively detected in all samples. Over 46% phosphopeptides were identified in at least three out of eight biological replicas. Comparison of AC3 KO and WT datasets revealed that phosphopeptides with motifs matching proline-directed kinases' recognition sites had a lower abundance in the KO dataset than in WTs. We detected 14 phosphopeptides restricted to WT dataset (i.e., Rabl6, Spast and Ppp1r14a) and 35 exclusively in KOs (i.e., Sptan1, Arhgap20, Arhgap44, and Pde1b). Moreover, 95 phosphopeptides (out of 90 proteins) were identified only in female dataset and 26 only in males. Label-free MS spectrum quantification using Skyline further identified phosphopeptides that had higher abundance in each sample group. In total, 204 proteins had sex-biased phosphorylation and 167 of them had increased expression in females relative to males. Interestingly, among the 204 gender-biased phosphoproteins, 31% were found to be associated with autism, including Dlg1, Dlgap2, Syn1, Syngap1, Ctnna1, Ctnnd1, Ctnnd2, Pkp4, and Arvcf. Therefore, this study also provides the first phosphoproteomics evidence suggesting that gender-biased post-translational phosphorylation may be implicated in the sexual dimorphism of autism.

Dataset Information

Ciliary Type III Adenylyl Cyclase in the VMH Is Crucial for High-Fat Diet-Induced Obesity Mediated by Autophagy.

Publications

Ciliary Type III Adenylyl Cyclase in the VMH Is Crucial for High-Fat Diet-Induced Obesity Mediated by Autophagy.

Similar Datasets

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