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

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Góralska J., Śliwa A., Gruca A., Raźny U., Chojnacka M., Polus A., Solnica B., Malczewska-Malec M.

2017

vol. 64

issue 3

423-429

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.

The catalytic activity of sirtuins in physiology and disease from the epigenetic point of view

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Albani D., Forloni G.

Epigenetics of Degenerative Diseases

2013

vol. 1

issue 1

Sirtuins are a family of conserved enzymes that are involved in physiological and pathological pathways and have been investigated in relation to the ageing process. There are seven different sirtuins in mammals that are encoded by individual genes (SIRT1-7). Sirtuins share a highly conserved catalytic domain, and they have NAD+ dependent deacetylase activity and secondary ADPribosylase activity in different proportions and on different molecular targets. Sirtuins might be pharmacologically modulated by small molecules that might represent a novel class of “epigenetic” drugs. In fact, sirtuins’ deacetylase activity may impact the epigenetic regulation network acting on histones or affecting chromatin stability, while the mono-ADP-ribosylase catalysis is less explored to this respect. Here we review and discuss the potential impact of sirtuin catalytic activities from the epigenetic pointof- view, with a focus on age-related diseases (cancer,

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1 Acta Biochimica Polonica

1 Epigenetics of Degenerative Diseases

1 2017

1 2014

1 Albani D.

1 Chojnacka M.

1 Forloni G.

1 Gruca A.

1 Góralska J.

1 Malczewska-Malec M.

1 Polus A.

1 Raźny U.

1 Solnica B.

1 Śliwa A.

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

The catalytic activity of sirtuins in physiology and disease from the epigenetic point of view