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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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Abstract

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 shortor 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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Abbreviations

ACC:

acetyl-CoA carboxylase

AGRP:

agouti-related peptide

AICAR:

5-aminoimidazole-4-carboxamide ribonucleotide

AMPK:

adenosine monophosphate-dependent protein kinase

CART:

cocaine- and amphetamine-regulated transcript

CB1R:

cannabinoid type 1 receptor

CCK:

cholecystokinin

EBSS:

Earl’s balanced salt solution

(F)FA:

(free) fatty acid

Glut4:

glucose transport isoform 4

HBSS:

Hank’s balanced salt solution

IBMX:

3-isobutyl-1-methylxanthine

MCH:

melanin-concentrating hormone

NPY:

neuropeptide Y

PKA:

protein kinase A

POMC:

proopiomelanocortin.

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Authors and Affiliations

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

    G. A. Müller

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

    G. A. Müller

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

    S. Wied & A. W. Herling

Authors
  1. G. A. Müller
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  2. S. Wied
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  3. A. W. Herling
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Correspondence to G. A. Müller.

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Conflict of interest. The authors declare no conflict of interest neither in financial nor in any other area.

Compliance with ethical standards. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM19-029, July 15, 2019.

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Müller, G.A., Wied, S. & Herling, A.W. Analysis of Direct Effects of the CB1 Receptor Antagonist Rimonabant on Fatty Acid Oxidation and Glycogenolysis in Liver and Muscle Cells in vitro. Biochemistry Moscow 84, 954–962 (2019). https://doi.org/10.1134/S000629791908011X

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  • DOI: https://doi.org/10.1134/S000629791908011X

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