A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
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ABSTRACT:
PROVIDER: PRJNA603578 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10981900.fastq.gz | Fastqsanger.gz | |||
| SRR10981901.fastq.gz | Fastqsanger.gz | |||
| SRR10981902.fastq.gz | Fastqsanger.gz | |||
| SRR10981903.fastq.gz | Fastqsanger.gz | |||
| SRR10981904.fastq.gz | Fastqsanger.gz |
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2021-08-11 | GSE144414 | GEO
Project description:Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
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Project description:Neurotransmitters have been well-documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrated that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-FAD-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of Bcl2l11 and Dusp2, lowering the formation of NLRP3-ASC-Caspase-1 complex. Meanwhile, GABA-succinate axis lowers succinylation of mitochondrial proteins to promote mitochondrial oxidative phosphorylation (OXPHOS). We also found that GABA alleviates the LPS-induced sepsis as well as high-fat diet-induced obesity in mice. Our study proves that GABA is potential in lessening the pro-inflammatory macrophage responses associating with metabolic reprogramming and protein succinylation, thus providing a strategy for treating macrophage-related inflammatory diseases.
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Project description:Background & Aims: Disturbed hepatic metabolism frequently results in excessive lipid accumulation in adipose. The causal mechanism underlying the interplay of the liver-adipose axis on how to maintain lipid homeostasis is not fully elucidated. This study investigated the role of hepatic Glucuronyl C5-epimerase (Glce) in obesity. Methods: We investigated the expression of Glce in liver of obese patients which were divided according to their body mass index (BMI). Obesity models were established in hepatic Glce-knockout and wild-type mice fed a high-fat diet (HFD) for 16 weeks. The role of Glce protein in the progression of disrupted hepatokine secretion was examined using a secretome analysis. Results: Hepatic Glce expression was inversely related to the BMI values of obese patients. Decreased Glce was also detected in an HFD murine model. Hepatic Glce deficiency led to impaired thermogenesis in adipose tissue and exacerbated diet-induced obesity. Intriguingly, reduced circulating growth differentiation factor 15 (GDF15) was observed in Glce-knockout mice. Treatment with recombinant GDF15 obstructed fat accumulation in the absence of Glce, an effect that was similar to the re-expression of Glce and its active site mutants both in vitro and in vivo. Furthermore, Glce deletion not only reduced GDF15 mature form but also disrupted the ubiquitination of GDF15 probably due to their interaction. Conclusions: Hepatic Glce deletion facilitates the obesity independent of its enzyme activity. Decreased Glce reduced the secretion of GDF15 which perturbed lipid homeostasis in vivo, highlighting the role of a novel Glce-GDF15 axis in energy balance which might be a potential target for combating obesity.
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