Intracerebroventricular Leptin Regulates Hepatic but Not Peripheral Glucose Fluxes

Abstract

). Here we examine whether intracerebroventricular (ICV) leptin administration regulates peripheral and hepatic insulin action. Recombinant mouse leptin (n ‫؍‬ 14; 0.02 or 1 g/kg⅐h) or vehicle (n ‫؍‬ 9) were administered ICV for 6 h to conscious rats, and insulin action was determined by insulin (3 milliunits/kg⅐min) clamp and tracer dilution techniques. During physiologic hyperinsulinemia (ϳ65 microunits/ml), the rates of glucose uptake (R d , 20.1 ؎ 0.6 and 23.1 ؎ 0.7 versus 21.7 ؎ 0.6 mg/kg⅐min; p ‫؍‬ NS), glycolysis and glycogen synthesis were similar in rats receiving low-and high-dose leptin versus vehicle. ICV leptin resulted in a 2-3-fold increase in hepatic phosphoenolpyruvate carboxykinase mRNA levels. Glycogenolysis and PEP-gluconeogenesis (2.1 ؎ 0.3 mg/ kg⅐min) contributed similarly to endogenous glucose production (GP) in the vehicle-infused group. However, gluconeogenesis accounted for ϳ80% of GP in both groups receiving ICV leptin, while hepatic glycogenolysis was markedly suppressed (0.7 ؎ 0.3 and 1.2 ؎ 0.3 versus 2.2 ؎ 0.4 mg/kg⅐min, in rats receiving low-and high-dose leptin versus vehicle, respectively; p < 0.01). In summary, short-term ICV leptin administration: 1) failed to affect peripheral insulin action, but 2) induced a striking re-distribution of intrahepatic glucose fluxes. The latter effect largely reproduced that of leptin given systemically at much higher doses. Thus, the regulation of hepatic glucose fluxes by leptin is largely mediated via its central receptors.Leptin, the protein encoded by the ob gene, is an anorectic hormone secreted by adipose cells (1-6). The effects of leptin on food intake are reproduced by its injection directly in the central nervous system, thus suggesting a prominent role of the hypothalamic receptors in mediating its actions (7-12). In the long term, circulating leptin levels correlate with adiposity (3,8,10,13,14) and leptin has been suggested to function as a "biochemical messenger" between fat depots and the hypothalamus (7,10,11,14,15).Nutritional and hormonal factors can also regulate ob gene expression in adipose cells and leptin levels in plasma (3,13,14,16,17). Most important, it has become increasingly evident that leptin plays in turn an important role in the regulation of carbohydrate and lipid metabolism (9, 14, 18 -24). We have recently demonstrated that marked and acute elevations in the plasma leptin concentrations modulate the hepatic gene expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) 1 and the rate of gluconeogenesis (22). It is presently unknown whether the latter metabolic effects of leptin are, at least in part, mediated through its action on hypothalamic receptors.Therefore the primary aim of this study was to examine the metabolic impact of intracerebroventricular (ICV) infusions of leptin on peripheral and hepatic glucose metabolism under basal conditions and in response to physiologic hyperinsulinemia. Furthermore, as recent studies have suggested that a highly selective ␤ 3 -adrenergic recep...

Chronic central administration of ghrelin reverses the effects of leptin

“…[13][14][15][16] We found that chronic central administration of leptin decreased fasting plasma glucose concentrations, a finding consistent with previous results showing that chronic central administration of leptin decreased fasting plasma glucose levels in normal and diabetic rats. 20 Centrally administered leptin has also been shown to stimulate glucose uptake to the peripheral tissue 13,14 and to increase glucose turnover, 15 which may result in decreased plasma glucose levels.…”

“…Central administration of leptin suppresses insulin secretion from the pancreas, 12 increases glucose uptake in peripheral tissues, and modulates hepatic glucose production. [13][14][15][16] Chronic intracerebroventricular (ICV) administration of ghrelin has been reported to increase the 24-h respiratory quotient without altering energy expenditure or locomotor activity. 3 It is not clear, however, if these alterations are associated with the changes in body weight and fat mass resulting from ICV administration of ghrelin.…”

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

“…Whether these actions of leptin are mediated directly or indirectly, however, remains controversial. 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.…”

“…Using [ 13 C]NMR, Cohen et al (50) have shown that leptin can acutely enhance hepatic glycogen synthesis in vivo, and leptin has been shown to enhance glycogen synthesis in isolated hepatocytes (51). This latter effect, however, seems to occur via an inhibition of phosphorylase rather than an increase in synthase activity (19).…”

“…In type 2 diabetes with fasting hyperglycemia, insulin resistance is manifest in decreased insulin stimulation of glucose uptake in muscle and fat and, most importantly, uncontrolled hepatic glucose output (24). In vivo, leptin has been shown to enhance insulin's ability to inhibit hepatic glucose output, increase gluconeogenesis, and suppress glycogenolysis, as well as to increase PEPCK and decrease glucokinase gene expression (12,13). Whether these actions of leptin are mediated directly or indirectly, however, remains controversial.…”