Acute Effect of Leptin on Hepatic Glycogenolysis and Gluconeogenesis in Perfused Rat Liver

Abstract

Leptin circulates in blood and is involved in body weight control primarily via hypothalamic receptors. To examine its direct metabolic action, effects of short-term portal leptin infusion: 1) on postprandial basal and epinephrine-stimulated glycogenolysis; and 2) on postabsorptive lactate-stimulated gluconeogenesis were studied in isolated perfused rat livers. Incremental epinephrine (150 pmol x min-1 x g-1 liver)-stimulated glucose release (in micromol/g liver within 30 minutes; control: 28.3 +/- 2.8) was suppressed (P <.05) by 44% (15.8 +/- 1.6), by 48% (14.6 +/- 4.1), and by 53% (13.3 +/- 2.1) during insulin (3 pmol x min-1 x g-1 liver), leptin (30 pmol x min-1 x g-1 liver), and simultaneous leptin + insulin infusion. Perfusate cyclic adenosine monophosphate increased approximately twofold during epinephrine stimulation in all groups. Neither leptin nor insulin affected hepatic lactate production, bile flow, or portal pressure in the fed state. In the postabsorptive state (20-hour fasting), rates of lactate (10 mmol/L)-dependent hepatic glucose release (in micromol. min-1 x g-1 liver; control: 0.12 +/- 0.01) were increased (P <.01) to 0.35 +/- 0.02 and to 0.24 +/- 0.01 by glucagon (3 pmol x min-1 x g-1 liver) and by leptin (15 pmol x min-1 x g-1 liver), respectively. In parallel, lactate uptake rates (in micromol x min-1 x g-1 liver) were higher in the presence of both glucagon (0.90 +/- 0. 03) and leptin (0.84 +/- 0.02) compared with control (0.68 +/- 0.04). In conclusion, leptin modulates hepatic glucose fluxes and may contribute to direct humoral regulation of liver glycogen stores in the fasted as well as in the fed state.

Selective interaction between leptin and insulin signaling pathways in a hepatic cell line

“…For example, a redistribution of hepatic glucose flux occurs after intracerebroventricular injection of leptin, suggesting a central and indirect action of leptin on liver (13). However, peripheral administration of leptin (13) and studies with isolated perfused liver (38) indicate the possibility of a direct action of leptin on this tissue. In addition, leptin effects and cross talk between the insulin and leptin signaling network have been demonstrated in vitro by using cultured human hepatoma cells, freshly isolated hepatocytes, and C 2 C 12 muscle cells (9,14,15,19).…”

“…Acute infusions of leptin in rats have also been shown to enhance insulin inhibition of hepatic glucose production, increase hepatic PEPCK mRNA, and decrease abundance of the glucokinase message (12). In perfused liver, leptin can mimic insulin action to suppress epinephrineinduced glucose release, while stimulating lactate-induced gluconeogenesis (38). In addition to its effects on glycogen synthase, GSK3 is involved in a great variety of cellular responses, including phosphorylation of ATP-citrate lyase and the transcription factors C͞EBP␣ and heat shock transcription factor 1 (31)(32)(33)52).…”

Gender difference in the leptin response to feeding in peroxisome-proliferator-activated receptor-alpha knockout mice

“…38 It also has effects on glucose metabolism, increasing peripheral glucose uptake and oxidation 39 and increasing hepatic glycogen stores. 40,41 Leptin itself inhibits insulin secretion in vitro. 11 Although in some studies in vitro leptin has been shown to impair the early steps of insulin action, 42 when leptin is administered in vivo there is an improvement in peripheral and hepatic insulin sensitivity 43,44 and this may involve convergence or synergism between leptin-and insulin-signal transduction.…”

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

“…6,7 Since obesity is frequently associated with insulin resistance eventually resulting in type 2 diabetes mellitus, 8 it is of interest whether or not plasma leptin concentration is also related to the diabetic metabolic state. Evidence has been provided that leptin is involved in the regulation of peripheral glucose metabolism at the level of the pancreatic bcell, 9,10 liver, 11 and fat cells. 12 Of note, insulin has been shown to stimulate ob gene expression and leptin secretion in cultured human adipocytes.…”