Studies with rodents have demonstrated that leptin induces lipolysis both in vitro [373, 374] and in vivo [375]. The effect was absent in animals lacking a functional leptin receptor, i.e. db/db mice [374, 375] and in Zucker rats [373]. Intriguingly, FA release does not accompany glycerol release in leptin-induced lipolysis, which suggests simultaneous induction of FA oxidation [369]. In these studies, effects on HSL expression were not investigated. Thus it is not known whether the lipolytic effect of leptin is mediated via phosphorylation-induced activation of HSL, an induction of HSL expression, a combination of both, or some other mechanism. In another study, however, long-term treatment of mice with leptin increased HSL mRNA expression by 30% in WAT, whereas no effect was seen in brown adipose tissue [376]. The leptin signal is presumably transduced via the JAK/STAT pathway. Leptin was also shown to directly activate the TAG/FA substrate cycle, lipolysis and FA oxidation, shifting fuel preference from carbohydrate to FA oxidation. In particular, studies with isolated rat adipocytes in primary culture demonstrated that leptin impairs insulin inhibition of isoproterenol-induced lipolysis and PKA activation [377]. These insulin effects were reduced by leptin (2 nM) with a half-life of 8 h. Leptin concentrations below 1 nM led to a right-ward shift of the corresponding insulin concentration-response curves. At leptin concentrations above 30 nM the responsiveness was diminished, and also resulted in nearly complete relief of lipolysis from insulin control. The IC50 for leptin was about 3 nM after 15 h of preincubation of the primary adipocytes. The natural splice variant des-Gln49-leptin exhibited a significantly lower potency. Adipocytes regained full sensitivity for insulin's antilipolytic action within a few hours after leptin removal [377]. Consequently, in ob/ob mice, the loss of leptin stimulation of uncoupling and TAG/FA substrate cycling triggered, at least in part, by leptin blockade of the protein-1 antilipolytic activity of insulin will simultaneously contribute to the decrease in TAG mobilization and utilization as well as to the increase in TAG synthesis and storage. In conclusion, accelerated TAG/FA substrate cycling in adipose tissue provides a new mechanism by which leptin triggers increased metabolic rate and energy expenditure.

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