Leptin action in peripheral tissues

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Ablation of the Arc, Lep/db/db, or loss of LEPRb in neurons and specifically in POMC neurons have all confirmed that leptin acts primarily in the brain (36,87-90).

Nonetheless, numerous studies have demonstrated leptin signaling in blood cells, pancreatic P-cells, pituitary, kidney, hepatocytes, muscle, and adipocytes (18,91-100). Apart from immune cells, most of these tissues lack functional LEPRb or at best express very low levels, suggesting that short-form leptin receptors may mediate leptin signaling (91-100). Ex vivo studies of isolated T-lymphocytes from mice and humans indicate that leptin promotes cellular survival and enhances immunity, especially during starvation (91). Leptin inhibits insulin secretion from isolated pancreatic islets, although the opposite effect has been reported (92,93). Furthermore, leptin induces LH and follicle-stimulating hormone (FSH) release from pituitary explants and sympathetic nerve activity to the kidneys (94,97).

Kim et al. (95) found that intravenously injected leptin increased STAT1 and STAT3 phosphorylation and, to a lesser extent, MAP-kinase and PI3-kinase, in adipose tissue. Leptin did not affect signaling in lepjdb/db mice, supporting a role for LEPRb in adipocyte leptin action (95). The latter is consistent with the presence of LEPR on human and rodent adipocytes (96). Leptin has no direct effect on glucose uptake in adipocytes, but induces lipolysis in adipose explants and isolated adipocytes (99-101). Furthermore, leptin antagonizes the effects of insulin to inhibit lipolysis; this response is abolished in Zucker fa/fa rats or Lep/^b/db mice, both of which lack functional leptin receptors (96,100). Direct effects of leptin on hepatic gluconeogenesis have been reported (102); however, a major role of leptin in the liver is doubtful, given the apparently normal phenotype of mice with targeted ablation of LEPR in the liver (88).

Minokoshi et al. (103) demonstrated a biphasic action of leptin on muscle after intravenous injection. The initial increase in AMPK activity in soleus muscle occurred rapidly within 15 min, and was not affected by sympathetic blockade (103). In contrast, a later, more sustained, increase in AMPK activation (60 min to 6 h) was mimicked by intrahypothalamic leptin injection and abolished by sympathetic blockade (103). A direct action of leptin was confirmed by incubating soleus muscle with and without leptin and demonstrating a robust leptin-dependent stimulation of AMPK activity. Direct or indirect activation of muscle LEPRb by leptin results in phosphorylation and activation of AMPK (103). AMPK phosphorylates acetyl-CoA carboxylase (ACC), leading to inhibition of ACC activity and thus decreasing formation of malonyl-CoA, which in turn disinhibits carnitine palmitoyltransferase 1 (CPT-1), a critical step for translocation of fatty acids into mitochondria to undergo ^-oxidation (104). It has been proposed that this leptin-AMPK pathway may play a role in protecting nonadipocytes from lipid accumulation (steatosis) and lipotoxicity (105). Obesity and aging are associated with leptin resistance, leading to steatosis, lipotoxicity, and pancreatic ^-cell failure, diabetes, cardiomyocellular damage, and dysfunction of various organs (105).

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