Butyrate and other short-chain fatty acids increase the rate of lipolysis in 3T3-L1 adipocytes.

John M Rumberger,Allan Green,Jonathan R.S Arch

doi:10.7717/peerj.611

John M Rumberger, Allan Green + Show 1 more

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https://doi.org/10.7717/peerj.611

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Abstract

We determined the effect of butyrate and other short-chain fatty acids (SCFA) on rates of lipolysis in 3T3-L1 adipocytes. Prolonged treatment with butyrate (5 mM) increased the rate of lipolysis approximately 2–3-fold. Aminobutyric acid and acetate had little or no effect on lipolysis, however propionate stimulated lipolysis, suggesting that butyrate and propionate act through their shared activity as histone deacetylase (HDAC) inhibitors. Consistent with this, the HDAC inhibitor trichostatin A (1 µM) also stimulated lipolysis to a similar extent as did butyrate. Western blot data suggested that neither mitogen-activated protein kinase (MAPK) activation nor perilipin down-regulation are necessary for SCFA-induced lipolysis. Stimulation of lipolysis with butyrate and trichostatin A was glucose-dependent. Changes in AMP-activated protein kinase (AMPK) phosphorylation mediated by glucose were independent of changes in rates of lipolysis. The glycolytic inhibitor iodoacetate prevented both butyrate- and tumor necrosis factor-alpha-(TNF-α) mediated increases in rates of lipolysis indicating glucose metabolism is required. However, unlike TNF-α– , butyrate-stimulated lipolysis was not associated with increased lactate release or inhibited by activation of pyruvate dehydrogenase (PDH) with dichloroacetate. These data demonstrate an important relationship between lipolytic activity and reported HDAC inhibitory activity of butyrate, other short-chain fatty acids and trichostatin A. Given that HDAC inhibitors are presently being evaluated for the treatment of diabetes and other disorders, more work will be essential to determine if these effects on lipolysis are due to inhibition of HDAC.

Highlights

High rates of adipose tissue lipolysis can lead to production of excess free fatty acids
We hypothesized that the known histone deacetylase (HDAC) inhibitory activity of butyrate underlies its lipolytic effect, and so we evaluated the effects of 20 mM propionate, a less potent HDAC inhibitor than butyrate, and 1 μM trichostatin A, a potent and specific small molecule HDAC inhibitor
These data demonstrate that neither MAP kinase activation nor perilipin down-regulation is necessary for increasing rates of lipolysis in 3T3-L1 adipocytes. This was of interest because we have previously reported that these events are not sufficient to allow increased lipolysis in the presence of TNF-α (Green et al, 2004). In those studies we showed that the effects of TNF-α on rates of lipolysis were dependent on the presence of glucose the effects on perilipin and mitogen-activated protein kinase phosphorylation were independent of glucose

Summary

Introduction

High rates of adipose tissue lipolysis can lead to production of excess free fatty acids. Excess free fatty acids increase the rate of hepatic glucose output, induce skeletal muscle insulin resistance, and have other adverse effects that contribute to development of diabetes and cardiovascular disease (Bergman & Ader, 2000; Ginsberg, 2000; Egan, Greene & Goodfriend, 2001). How to cite this article Rumberger et al (2014), Butyrate and other short-chain fatty acids increase the rate of lipolysis in 3T3-L1 adipocytes. Near millimolar concentrations of butyrate are found in the hepatic portal vein, and concentrations in vivo may be physiologically significant for the regulation of adipocyte β-adrenergic receptor gene expression (Bergman, 1990; Krief et al, 1994). It has been reported that SCFA influence lipid metabolism, β-adrenergic receptor concentrations, and leptin production (Krief et al, 1994; Ding et al, 2000; Metz, Lopes-Cardoza & Van den Berg, 1974; Xiong et al, 2004)

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