Sensitivity of adipocyte lipolysis to stimulatory and inhibitory agonists in hypothyroidism and starvation

Abstract

1. The responsiveness of lipolysis to the stimulatory agonists noradrenaline, corticotropin and glucagon and to the inhibitory agonists N6-phenylisopropyladenosine, prostaglandin E1 and nicotinic acid was investigated with rat white adipocytes incubated with a high concentration of adenosine deaminase (1 unit/ml). 2. The cells were obtained from fed or 48 h-starved euthyroid animals or from fed or starved animals rendered hypothyroid by 4 weeks of treatment with low-iodine diet and propylthiouracil. 3. Hypothyroidism increased sensitivity to and efficacy of all three inhibitory agonists in their opposition of noradrenaline-stimulated lipolysis. Starvation decreased sensitivity to all three inhibitory agonists when opposing basal lipolysis. 4. Hypothyroidism decreased sensitivity to noradrenaline, glucagon and corticotropin by 37-, 4-and 4-fold respectively and decreased the maximum response to these agonists by approx. 50%, 50% and 75% respectively. Starvation reversed decreases in maximum response to these agonists in hypothyroidism. 5. Starvation in the euthyroid state increased sensitivity to glucagon and noradrenaline, but did not alter sensitivity to corticotropin. 6. Cells from hypothyroid rats were relatively insensitive to Bordetella pertussis toxin, which substantially increased basal lipolysis in the euthyroid state. INTRODUCTIONLipolysis in adipose tissue can be stimulated by the catecholamines, corticotropin and glucagon. Conversely, other agonists, e.g. adenosine, E-series prostaglandins and nicotinic acid, act through specific receptors to inhibit lipolysis. The activity of hormone-sensitive lipase is dependent on protein phosphorylation, which is the resultant of the activities of cyclic AMP-dependent protein kinase and phosphoprotein phosphatase(s). In turn, the cellular content of cyclic AMP is dependent on the relative activities of adenylate cyclase and cyclic nucleotide phosphodiesterase. Receptors for the inhibitory agonists are coupled to adenylate cyclase by a guanine nucleotide-binding protein (N1) distinct from that (N.) which couples receptors for stimulatory agonists to the enzyme (Rodbell, 1980;Murayama & Ui, 1983;Olansky et al., 1983;Moreno et al., 1983;Bokoch et al., 1984;Codina et al., 1984). In hypothyroidism adenylate cyclase, the increase in cyclic AMP, and lipolysis all show diminished responsiveness to the stimulatory agonists (Goodman & Bray, 1966;Armstrong et al., 1974;Correze et al., 1974;Malbon et al., 1978;Ohisalo & Stouffer, 1979;Goswami & Rosenberg, 1980). Conversely, the inhibitory effect of adenosine mediated by the A1 (Van Calker et al., 1979) or Ri (Londos et al., 1980) adenosine receptor is increased in hypothyroidism (Ohisalo & Stouffer, 1979;Malbon & Graziano, 1983;Chohan et al., 1984;Malbon et al., 1985). This enhanced responsiveness is most easily measured in the presence of adenosine deaminase by using the non-metabolized analogue PIA and appears to reflect an increase in the abundance of Ni in the adipocyte plasma membrane (Malbon et al., 1985) without any in...

Malarial toxic antigens synergistically enhance insulin signalling

“…Suppression can be overcome, however, by the addition of low concentrations of adenosine deaminase (ADas¢). This enzyme removes adenosine [13,14] (which is endogenous to the adipocyte incubation system [15]), increases responsiveness to insulin [14,16], and causes tonic inhibition of iipolysis through O~ [17,18]. TMA preparations alone did not affect noradrenalinc-stimulated lipolysis (results not shown), but when the maximal inhibition of lipolysis by insulin was attenuated by ADasc at 1 mU/ml, they induced a small, but significant, enhancement of insulin action (Fig.…”

Effects of diet on lipolysis and its regulation

“…In addition Saggerson (1986) reported an increased sensitivity to glucagon but not ACTH in fat cells from fasted rats. Fasting did not increase maximum response to catecholamines in isolated fat cells from humans (Andrews et al 1984), in perfused canine adipose tissue (Fredholm et al 1973) and in some studies with rat (Zapf et al 1977;Dax et al 1981;Saggerson, 1986) fat cells. Another study with rats suggests that fasting results in a reduced response to noradrenaline (Giudicelli et al 1982).…”

A novel assay for 5′-nucleotidase using 1,N6-etheno-AMP as substrate, and comments on the properties of the reaction product, ethenoadenosine

“…Measurements of white-adipocyte lipolysis and brown-adipocyte 02 uptake were made as described by Saggerson (1986) and Woodward & Saggerson (1986) respectively. T.I.c.…”

“…Effects of ethenoadenosine at adipocyte adenosine receptors Ifetheno-AMP were to be used to assay 5'-nucleotidase in whole-tissue preparations, it is of use to know whether the resulting ethenoadenosine has effects at tissue adenosine receptors which could cause extensive changes in tissue metabolism. Adenosine is antilipolytic in white and brown adipose tissues, and decreases 02 uptake in brown adipocytes (Saggerson, 1986;Woodward & Saggerson, 1986), and these effects appear to be mediated through Al-type receptors. Fig.…”