AJP - Endocrinology and Metabolism, Vol 262, Issue 2 E142-E149, Copyright © 1992 by American Physiological Society
Role of cAMP in mediating effects of fasting on dephosphorylation of insulin receptor
N. Begum, A. L. Graham, K. E. Sussman and B. Draznin
Department of Medicine, Veterans Administration Medical Center, Denver, Colorado.
We studied the effect of fasting on phosphotyrosine phosphatase (PTPase)
activities in particulate (PF) and cytosolic (CF) fractions of rat
adipocytes and liver. PTPase activity was assessed using [32P]tyrosine
insulin receptor (IR). In adipocytes, 48 h fasting significantly inhibited
PTPase activity. Dephosphorylation of IR by PF and CF PTPases was reduced
by 80 and 65%, respectively. Similar reductions of lesser magnitude were
observed in fasted rat livers. The effect of fasting was completely
reversed by either refeeding or by incubating "fasted" adipocytes for 2 h
in tissue culture medium containing 5 mM glucose. Neither 20 mM glucose nor
the presence of insulin influenced phosphatase activity. Because fasting is
accompanied by elevated protein kinase C (PKC) and adenosine 3',5'-cyclic
monophosphate (cAMP) levels, we examined their influence on adipocyte
PTPases. Neither activation (1 microM 12-O-tetradecanoylphorbol-13-acetate)
nor inhibition (20 microM sphingosine) of PKC affected PTPase activity. In
contrast, cAMP (2 mM) significantly inhibited PTPase activity (80%
inhibition at 2 h), and its effect was prevented by a cAMP antagonist
RpcAMP. Fasting- and cAMP-induced inhibition of PTPase activity was
restored by incubating PF with trypsin (4 micrograms/ml for 5 min), which
separated the putative inhibitors from the phosphatases. We conclude that
fasting-induced inhibition of PTPases is mediated by elevated cAMP levels,
most likely by activating phosphatase inhibitors.
