Leptin Impairs Insulin Signaling in Rat Adipocytes

Abstract

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3␤ phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3␤ phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity. Diabetes 53

Plasma Leptin Levels in Rats with Pancreatitis

“…In several recent studies, it has also been shown that leptin has a profound inhibitory influence upon insulin secretion by acting directly on the pancreatic betacells (Jaworek et al 2003;Perez et al 2004). In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance."…”

“…Leptin was first described to act on the satiety center in the hypothalamus through specific receptors to restrict food intake and enhance energy expenditure (Konturek et al 2001). It has also been demonstrated that leptin has some peripheral effects such as inhibition of insulin biosynthesis and secretion in pancreatic beta-cells (Jaworek et al 2003;Benomar et al 2004;Perez et al 2004). In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance."…”

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

“…Five-and 21-month-old rats were randomly selected to undergo a food restriction protocol as described earlier (Pérez et al 2004). They were placed in individual cages and fed daily 18 and 21 g of chow respectively (equivalent to z80% of normal food intake).…”

Glucemia y concentraciones de insulina en sangre de ratas Wistar sometidas a dieta alta en grasa y a tratamiento con péptidos miméticos de leptina

“…Los estudios en ratones knock out para el gen de leptina demostraron una asociación entre leptina, obesidad y otras secuelas metabólicas, tales como hiperfagia e hiperglucemia (16,17); posteriormente, se realizaron diversos estudios que, además de asociarla con obesidad tanto en humanos como en ratas, la relacionan con cambios en las concentraciones y expresión de la insulina, lo cual podría explicar la fisiología y patología de la diabetes mellitus no insulino dependiente en la obesidad (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35); algunos de estos estudios sustentan sus conclusiones en lo siguiente: 1) Durante la pérdida de peso se observan disminuciones en la leptina con reducción en las concentraciones de insulina e independientemente de los cambios de adiposidad (21,26).…”

“…4) En las ratas Wistar con concentraciones plasmáticas elevadas de leptina se inhibe la señalización ejercida por la insulina en el adipocito al dañar el proceso de autofosforilación de su receptor, lo anterior parece estar relacionado con el incremento en la expresión de la proteína SOCS-3 (31).…”