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Abstract
Gut-derived short-chain fatty acids (SCFA), formed by microbial fermentation of dietary fibers, are believed to be involved in the etiology of obesity and diabetes. Previous data from our group showed that colonic infusions of physiologically relevant SCFA mixtures attenuated whole-body lipolysis in overweight men. To further study potential mechanisms involved in the antilipolytic properties of SCFA, we aimed to investigate the in vitro effects of SCFA incubations on intracellular lipolysis and signaling using a human white adipocyte model, the human multipotent adipose tissue-derived stem (hMADS) cells. hMADS adipocytes were incubated with mixtures of acetate, propionate, and butyrate or single SCFA (acetate, propionate and butyrate) in concentrations ranging between 1 µmol/L and 1 mmol/L. Glycerol release and lipase activation was investigated during basal conditions and following β-adrenergic stimulation. SCFA mixtures high in acetate and propionate decreased basal glycerol release, when compared to control (P < 0.05), while mixtures high in butyrate had no effect. Also, β-adrenergic receptor mediated glycerol release was not significantly altered following incubation with SCFA mixtures. Incubation with only acetate decreased basal (1 µmol/L) and β-adrenergically (1 µmol/L and 1 mmol/L) mediated glycerol release when compared with control (P < 0.05). In contrast, butyrate (1 µmol/L) slightly increased basal and β-adrenergically mediated glycerol release compared with control (P < 0.05), while propionate had no effect on lipolysis. The antilipolytic effect of acetate was accompanied by a reduced phosphorylation of hormone-sensitive lipase (HSL) at serine residue 650. In addition, inhibition of Gi G proteins following pertussis toxin treatment prevented the antilipolytic effect of acetate. The present data demonstrated that acetate was mainly responsible for the antilipolytic effects of SCFA and acts via attenuation of HSL phosphorylation in a Gi-coupled manner in hMADS adipocytes. Therefore, the modulation of colonic and circulating acetate may be an important target to modulate human adipose tissue lipid metabolism.
Highlights
Increasing evidence suggests that the human gut microbiota and its products are key players in host metabolism, body weight, and insulin sensitivity, thereby contributing to the etiology of obesity and related disorders [1]
We previously showed that acute colonic administration of three physiological-relevant short-chain fatty acids (SCFA) mixtures, and subsequent elevated circulating acetate concentrations, reduced circulating glycerol concentration in overweight males, indicative of a reduced whole-body lipolysis [19]
To further investigate whether the reduction in whole-body lipolysis was related to a putative SCFA effect on white adipocyte intracellular lipolysis, we performed several in vitro experiments using our validated human multipotent adipose tissue-derived stem (hMADS) adipocyte model
Summary
Increasing evidence suggests that the human gut microbiota and its products are key players in host metabolism, body weight, and insulin sensitivity, thereby contributing to the etiology of obesity and related disorders [1]. The gut microbiota can ferment indigestible nutrients into short-chain fatty acids (SCFA), of which acetate, propionate and butyrate are the most abundant [2] Of note, these SCFA can be taken up by the epithelial lining of the gut and released into the blood stream [3]. The adipose tissue thereby prevents excessive supply of lipids to nonadipose tissues such as liver, skeletal muscle, and pancreas This buffering action may be impaired under obese insulin-resistant conditions [6, 7], resulting in increased circulating lipids and ectopic fat storage in nonadipose tissues, thereby provoking disturbances in insulin signaling and substrate metabolism [8, 9]. To further study potential mechanisms involved in the antilipolytic properties of SCFA, we aimed to investigate the in vitro effects of SCFA incubations on intracellular lipolysis and signaling using a human white adipocyte model, the human multipotent adipose tissue-derived stem (hMADS) cells
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