Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function

Bricambert, Julien; Favre, D.; Brajkovic, Saska; Bonnefond, Amélie; Boutry, Raphaël; Salvi, Roberto; Plaisance, Valérie; Chikri, Mohamed; Chinetti-Gbaguidi, Giulia; Staels, Bart; Giusti, Vittorio; Caïazzo, Robert; Pattou, François; Waeber, Gérard; Froguel, Philippe; Abderrahmani, Amar

doi:10.1016/j.molmet.2016.09.011

Cited by 27 publications

(14 citation statements)

References 46 publications

(82 reference statements)

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“…In a recent paper, total HDAC activity was reported to be decreased in visceral adipose tissue of obese human subjects when compared to normal weight subjects. Decreased Hdac5 and Hdac6 expression has been shown in adipocytes from obese human subjects, as well as from obese mice (Bricambert et al, 2016). Activation of sirtuins by exendin-4 was also observed in hepatocytes and rat retinal cells (Lee et al, 2014;Zeng et al, 2016).…”

Section: Discussionmentioning

confidence: 86%

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

et al. 2017

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Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are relatively new pharmacological agents used to normalize glucose level in type 2 diabetes. Recently, GLP-1RAs have been approved for the treatment of obesity to reduce body weight in non-diabetic patients. The extra-pancre-atic effects of GLP-1RAs, as well as their molecular mechanism of action, are still poorly understood. Thus this study was aimed to verify the hypothesis that the mechanism of action of the GLP-1RAs involves mitochondria and that GLP-1RAs administration can improve mitochondrial functions. For this purpose, preadipocytes CHUBS7 were differentiated to mature adipocytes and then stimulated with GLP-1RA, exendin-4 at 100 nM for 24 h. Oxygen consumption rates, mitochondrial membrane potential, intracellular ATP (adenosine triphosphate) level, SIRT1 and SIRT3 gene expression and the histone deacetylases' activity were measured. Exendin-4 was found to uncouple mitochondrial electron transport from ATP synthesis, slightly decreasing mitochondrial membrane potential in mature adipocytes. Routine respiration and uncoupled oxy- gen consumption rates were higher in exendin-4 treated adipocytes than in the non-treated cells. The ATP level remained unchanged. Exendin-4 enhanced SIRT1 and SIRT3 genes expression. Histone deacetylases' activity in the nuclear fraction was not affected by exendin-4, although the activity of class III histone deacetylases was increased. All of the effects on mitochondrial bioenergetics induced by exendin-4 were abolished by addition of glucagon-like peptide 1 receptor antagonist. In conclusion, exendin-4 activates the sirtuin pathway and increases energy expenditure in human adipocytes. Our results suggest another mechanism that may be responsible for body weight reduction observed in patients using GLP-1RAs.

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Section: Discussionmentioning

confidence: 86%

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

et al. 2017

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“…Additionally, excessive adipocyte hypertrophy without proper neovascularization creates a pseudohypoxic state in the adipose tissue [65] , [66] . Altogether, these stimuli lead to the infiltration of immune cells into the adipose tissue [67] , [68] . Within the tissue, monocytes differentiate into either anti-inflammatory M2 or pro-inflammatory M1 macrophages depending on the niche [69] .…”

Section: The Etiopathogenesis Of Metabolic Diseasesmentioning

confidence: 99%

Shortcuts to a functional adipose tissue: The role of small non-coding RNAs

2017

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Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit – the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals.

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“…For Class II HDACs, high HDAC5 and HDAC6 expression levels are required for adequate adipocyte function [ 8 ]. HDAC9 gene deletion prevents the detrimental effects of chronic high-fat feeding on adipogenic differentiation, increases adiponectin expression, and enhances energy expenditure by promoting beige adipogenesis, thus leading to reduced body mass and improved metabolic homeostasis [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Programming and Regulation of Metabolic Homeostasis by HDAC11

Sun

Evsikova²,

Bian

et al. 2018

EBioMedicine

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Histone deacetylases (HDACs) are enzymes that regulate protein functions by catalyzing the removal of acetyl and acyl groups from lysine residues. They play pivotal roles in governing cell behaviors and are indispensable in numerous biological processes. HDAC11, the last identified and sole member of class IV HDACs, was reported over a decade ago. However, its physiological function remains poorly understood. Here, we report that HDAC11 knockout mice are resistant to high-fat diet-induced obesity and metabolic syndrome, suggesting that HDAC11 functions as a crucial metabolic regulator. Depletion of HDAC11 significantly enhanced insulin sensitivity and glucose tolerance, attenuated hypercholesterolemia, and decreased hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. Overall, our findings distinguish HDAC11 as a novel regulator of obesity, with potentially important implications for obesity-related disease treatment.

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Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function

Cited by 27 publications

References 46 publications

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

Shortcuts to a functional adipose tissue: The role of small non-coding RNAs

Programming and Regulation of Metabolic Homeostasis by HDAC11

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