Leptin‐induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes

Abstract

The aim of the present study was to gain insight into the signaling pathway used by leptin to stimulate lipolysis. The lipolytic rate of white adipocytes from sex-and age-matched lean (؉/؉) and fa/fa rats was determined in the absence or presence of leptin together with a number of agents acting at different levels of the signaling cascade. Leptin did not modify FSK-, dbcAMP-, and IBMX-stimulated lipolysis. Lipolysis can also be maximally stimulated by lowering media adenosine levels with adenosine deaminase (ADA), i.e., in the ligand-free state. Although ADA produced near maximal lipolysis in adipocytes of lean animals, only half of the maximal lipolytic rate (50.9؎3.2%) was achieved in fat cells from fa/fa rats (P‫.)4300.0؍‬ In adipocytes from lean animals preincubated with ADA, leptin caused a concentration-related stimulation of lipolysis (P‫.)1000.0؍‬ However, leptin had no effect on the lipolytic activity of adipocytes in the ligand-free state from fa/fa rats. The adenosine A 1 receptor agonist CPA effectively inhibited basal lipolysis in both lean and obese adipocytes (P‫1000.0؍‬ and P‫,0900.0؍‬ respectively). Leptin had no effect on the lipolytic rate of adipocytes isolated from fa/fa rats and preincubated with CPA. When adipocytes were incubated with the A 1 receptor antagonist DPCPX, a significant increase in glycerol release was observed in fa/fa fat cells (P‫,)900.0؍‬ whereas cells isolated from lean rats showed no differences to ADA-stimulated lipolysis. After pretreatment with PTX, which inactivates receptor-mediated G i function, adipocytes of obese rats became as responsive to the stimulatory actions of ISO as cells from lean rats (P‫0900.0؍‬ vs. ISO in fa/fa rats; P‫6142.0؍‬ vs. lean rats, respectively). PTX treatment of lean cells, however, did not alter their response to this lipolytic agent. It can be concluded that the lipolytic effect of leptin is located at the adenylate cyclase/G i proteins level and that leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes.-Frühbeck, G., Gómez-Ambrosi, J., Salvador, J. Leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes. FASEB J. 15, 333-340 (2001)

Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice

“…It is well known that lipolysis is induced by various hormones and cytokines in adipocytes (Carmen & Victor 2006). Furthermore, this lipolysis was also stimulated by forskolin, isobutyl-methylxanthine (IBMX) or dibutyrylcAMP in adipocytes prepared from lean or obese Zucker rats (Fruhbeck et al 2001), indicating that the lipolysis is regulated by intracellular cAMP levels. As Gpbar1 also stimulates cAMP formation, Gpbar1 may play a role in the regulation of the lipolysis in WAT; however, further investigation is required.…”

Effect of placental function on fatty acid requirements during pregnancy

“…Placentally derived leptin is a potent stimulator of lipolysis (Masuzaki et al, 1997;Gomez et al, 1999;Fruhbeck et al, 2001) which the human placenta exports into both the maternal and fetal circulation (Linnemann et al, 2000;Hoggard et al, 2001). The rate of placental leptin export into the maternal circulation increases with increasing fetal to placental weight ratio (Hoggard et al, 2001), suggesting that the placenta may modulate its own substrate supply in response to the fetal demand.…”

Physiological regulation of NEFA availability: lipolysis pathway

“…Recently, the lipolysisstimulating actions of a number of cytokines secreted in the adipose tissue have been described, including those of leptin (Fruhbeck et al 2001), TNF-a and IL-6 (Lyngso et al 2002). The physiological relevance of the lipolytic action of these substances remains to be elucidated.…”