G. Mory et al., Impaired beta-adrenergic signaling pathway in white adipocytes of sucklingfa/fa Zucker rats: a defect in receptor coupling, INT J OBES, 25(11), 2001, pp. 1592-1598
BACKGROUND: In fa/fa Zucker rats, leptin receptor deficiency is responsible
for both a deficit of energy expenditure and hyperphagia which lead to mas
sive obesity and insulin resistance in adulthood. This obesity is also char
acterised by alterations of the beta -adrenergic signaling pathway.
OBJECTIVE: To determine whether alterations in beta -adrenergic pathway cou
ld occur at the onset of obesity when fa/fa rats are not yet hyperinsulinem
ic.
ANIMALS: Fourteen-day-old suckling fa/fa and Fa/fa littermates (from hetero
zygous lean (Fa/fa) female and homozygous obese (fa/fa) male mating).
MEASUREMENTS: Membranes were prepared from isolated adipocytes after collag
enase treatment of inguinal adipose tissue. The response of adenylyl-cyclas
e activity to stimulation by isoprenaline, GTP gamma -S or forskolin was st
udied. B-max and K-d of (beta (1) + beta (2)) and of beta (3) adrenoceptors
were measured using H-3-CGP saturation binding experiments. mRNA concentra
tion of beta (1) and beta (3)-AR was determined by semi-quantitative RT-PCR
. G(s)alpha protein was quantified by Western blotting and Gi protein by AD
P-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 enti
rely accounted for by fat cell hypertrophy (x2.5 in volume). In fa/fa compa
red to Falfa pups, response of adenylyl cyclase to isoprenaline was decreas
ed two-fold but responses to GTP(gamma)S or forskolin were unchanged. Densi
ty Of (beta (1) + beta (2)) and beta (3)-AR was not affected by the fa/fa g
enotype, as well as G(s)alpha and Gi concentration.
CONCLUSION: Response of inguinal fat cells to catecholamines was decreased
without any quantitative modifications of the different elements of the ade
nylyl cyclase cascade. This suggests an alteration in the coupling between
beta -AR and G proteins. Due to the important increase in fat cell volume w
e hypothesize that changes in the physical properties of plasma membranes a
nd/or changes in cytoskeleton - extracellular-matrix interactions could dis
turb the beta -adrenergic pathway responsiveness. In addition to the excess
of lipid storage, which occurs very early at the onset of obesity, the imp
airment of the responsiveness to catecholamines reported in this study migh
t worsen the obesity syndrome.