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Impaired β-adrenergic signaling pathway in white adipocytes of suckling fa/fa Zucker rats: a defect in receptor coupling

International Journal of Obesity volume 25, pages 1592–1598 (2001)Cite this article

Abstract

BACKGROUND: In fa/fa Zucker rats, leptin receptor deficiency is responsible for both a deficit of energy expenditure and hyperphagia which lead to massive obesity and insulin resistance in adulthood. This obesity is also characterised by alterations of the β-adrenergic signaling pathway.

OBJECTIVE: To determine whether alterations in β-adrenergic pathway could occur at the onset of obesity when fa/fa rats are not yet hyperinsulinemic.

ANIMALS: Fourteen-day-old suckling fa/fa and Fa/fa littermates (from heterozygous lean (Fa/fa) female and homozygous obese (fa/fa) male mating).

MEASUREMENTS: Membranes were prepared from isolated adipocytes after collagenase treatment of inguinal adipose tissue. The response of adenylyl-cyclase activity to stimulation by isoprenaline, GTPγ-S or forskolin was studied. Bmax and Kd of (β1+β2) and of β3 adrenoceptors were measured using 3H-CGP saturation binding experiments. mRNA concentration of β1- and β3-AR was determined by semi-quantitative RT-PCR. Gsα protein was quantified by Western blotting and Gi protein by ADP-ribosylation.

RESULTS: Despite an almost normal body weight, inguinal fat pad weight was increased two-fold by the expression of fa mutation. This increase was entirely accounted for by fat cell hypertrophy (×2.5 in volume). In fa/fa compared to Fa/fa pups, response of adenylyl cyclase to isoprenaline was decreased two-fold but responses to GTPγS or forskolin were unchanged. Density of (β1+β2) and β3-AR was not affected by the fa/fa genotype, as well as Gsα and Gi concentration.

CONCLUSION: Response of inguinal fat cells to catecholamines was decreased without any quantitative modifications of the different elements of the adenylyl cyclase cascade. This suggests an alteration in the coupling between β-AR and G proteins. Due to the important increase in fat cell volume we hypothesize that changes in the physical properties of plasma membranes and/or changes in cytoskeleton–extracellular-matrix interactions could disturb the β-adrenergic pathway responsiveness. In addition to the excess of lipid storage, which occurs very early at the onset of obesity, the impairment of the responsiveness to catecholamines reported in this study might worsen the obesity syndrome.

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Authors and Affiliations

  1. INSERM U 465, Centre Biomédical des Cordeliers, Paris, France

    G Mory, M Wiel, H Adli, F Diot-Dupuy, P Ferré & R Bazin

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Correspondence to R Bazin.

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Mory, G., Wiel, M., Adli, H. et al. Impaired β-adrenergic signaling pathway in white adipocytes of suckling fa/fa Zucker rats: a defect in receptor coupling. Int J Obes 25, 1592–1598 (2001). https://doi.org/10.1038/sj.ijo.0801811

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