Analysis of Direct Effects of the CB1 Receptor Antagonist Rimonabant on Fatty Acid Oxidation and Glycogenolysis in Liver and Muscle Cells in vitro

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G. A. Müller^1,2,a*, S. Wied³, and A. W. Herling³

¹Helmholtz Diabetes Center (HDC) at the Helmholtz Center for Health and Environment Munich, Institute for Diabetes and Obesity (IDO), 85764 Oberschleissheim, Germany

²Ludwig-Maximilians-University of Munich, Department Biology I, Genetics, 82152 Planegg-Martinsried, Germany

³Sanofi Pharma Germany GmbH, Diabetes Research, 65926 Frankfurt am Main, Germany

^* To whom correspondence should be addressed.

Received February 4, 2019; Revised June 24, 2019; Accepted June 25, 2019

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Recent pharmacological findings regarding rimonabant, an anorectic and cannabinoid type 1 receptor (CB1R) antagonist, strongly suggest that some of its effects on the metabolic parameters and energy balance in rats are not related to the centrally mediated reduction in caloric intake. Instead, they may be associated with acute induction of glycogenolysis in the liver, in combination with transient increase in glucose oxidation and persistent increase in fat oxidation. It is possible that rimonabant produced direct short- or long-term stimulatory effect on these processes in primary and cultured rat cells. Rimonabant slightly stimulated β-oxidation of long-chain fatty acids in cultured rat myocytes overexpressing glucose transporter isoform 4, as well as activated phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK) in primary rat hepatocytes upon long-term incubation. However, short-term action of rimonabant failed to stimulate β-oxidation in myocytes, myotubes, and hepatocytes, as well as to upregulate AMPK phosphorylation, glycogenolysis, and cAMP levels in hepatocytes. As a consequence, the acute effects of rimonabant on hepatic glycogen content (reduction) and total energy expenditure (increase) in rats fed with a standard diet cannot be explained by direct stimulation of glycogenolysis and fatty acid oxidation in muscles and liver. Rather, these effects seem to be centrally mediated.

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KEY WORDS: AMP- and cAMP-dependent signaling, cannabinoid receptor 1, glucose and lipid metabolism, obesity

DOI: 10.1134/S000629791908011X

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