Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats

Abstract

White. Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 282: E1084-E1091, 2002; 10.1152/ajpendo.00489.2001.-This study examined the effect of intracerebroventricular leptin on insulin sensitivity in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were cannulated in the lateral ventricle and, after recovery, administered either intravenous STZ (50 mg/kg) to induce diabetes or citrate buffer. Chronic leptin (10 g/10 l icv) or vehicle injections were administered daily for 14 days beginning 2 days after establishment of hyperglycemia in the diabetic animals. At the end of the 2 wk of injections, insulin sensitivity was measured by the steady-state plasma glucose (SSPG) method. Blood glucose concentrations were dramatically reduced and normalized by the 4th day in diabetic animals receiving intracerebroventricular leptin treatment. Diabetic animals exhibited insulin resistance, whereas intracerebroventricular leptin significantly enhanced insulin sensitivity, as indicated by decreased SSPG. Circulating leptin levels were not increased in animals injected with intracerebroventricular leptin. Thus the increased peripheral insulin sensitivity appears to be due solely to the presence of leptin in the brain, not to leptin acting peripherally. These data imply that inadequate central leptin signaling may lead to insulin resistance. intracerebroventricular leptin; insulin resistance; hyperglycemia THE INTERACTION BETWEEN LEPTIN AND INSULIN has been the subject of several investigations. Leptin is thought to be a signal that informs the brain about the size of the fat mass in the body. It acts as a satiety factor, decreasing food intake and increasing energy expenditure, or at least preventing the decrease in energy expenditure normally associated with a decrease in food intake (38). These effects lead to a decrease in body fat. In addition to these actions, leptin treatment enhances insulin sensitivity in normal rats, as indicated by increased insulin-stimulated glucose utilization in peripheral tissues (7,33,42). It also decreases plasma glucose and/or insulin concentrations of normal animals in the postabsorptive state. Leptin has been shown to directly inhibit insulin secretion (11), whereas insulin increases leptin release from adipocytes (25). Evidence indicates that glucose metabolism, rather than insulin itself, is the main determinant for leptin expression in adipose tissue (22). Moreover, in vivo and in vitro evidence suggests that leptin and insulin-signaling networks may be connected at several levels, such as insulin receptor substrates, or IRS; phosphatidylinositol 3-kinase, or PI 3-kinase; and mitogen-activated protein kinase, or MAPK (19,20,41). Therefore, leptin and insulin-signaling pathways may interact with each other.The effects of leptin on insulin sensitivity have been examined independently of peripheral insulin concentrations. Diabetic animals induced by streptozotocin (STZ), which selectively destroys insulin-producing...

The role of leptin in diabetes: metabolic effects

“…In support of this, leptin administration directly into the brain, at doses that have no effect when administered peripherally, normalises blood glucose levels in rodent models of uDM [19][20][21][22]. This glucose-lowering effect of leptin occurs via a mechanism that is independent of reduced food intake, increased urinary glucose loss or recovery of pancreatic beta cells.…”

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

“…The direct effects of leptin on glucose metabolism and insulin signaling have not yet been fully elucidated. However, in vivo studies have shown that leptin improves insulin sensitivity (Ebihara et al, 2001;Lin et al, 2002;Ogawa et al, 1999;Yamauchi et al, 2001) and normalize glucose metabolism in rodents (Chinookoswong et al, 1999;Masuzaki et al, 1999). Transgenic expression of neuron-specific leptin receptor in receptor-deficient mice leads to amelioration of diabetes (de Luca et al, 2005).…”

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

“…56 The combined effects of the leptin therapy viz increased glucose metabolism and disposal by enhancing GLUT1 and GLUT4 in brown adipose tissue, liver and skeletal muscle asserted by increased leptin signaling along the FAN pathway, together with increased nonshivering thermogenic energy expenditure via EEN as evidenced by enhanced-brown adipose tissue UCP-1 mRNA, seemingly assisted in sustaining euglycemia in these mice. 38,55,56,91,92 Also, hyperleptinemia produced by systemic administration of Ad-lep in three type 1 diabetic rodents resulting from a loss of pancreatic b-cells either inflicted by autoimmune disease as in NOD (non-obese diabetic) mice, or chemically with streptozotocin or alloxan injections, corrected the severe hyperglycemia which was, however, transient paralleling the course of receding hyperleptenimia. 93 The efficacy of circulating leptin was also shown in these paradigms when intravenous infusion of leptin itself for 12 days rapidly impelled normoglycemia with a time course quite similar to that evoked by insulin replacement 94,95 Furthermore, the possibility that restoration of optimal hypothalamic leptin signaling alone imposed euglycemia in these paradigms was verified when leptin supply was endogenously generated solely in the hypothalamus of hyperglycemic streptozotocin-treated mice.…”

“…2,8,10,15,23,33,34 In this context, recent attention has been devoted to the disclosure that dynamic physiological fluctuations in circulating titers of leptin, a hormone produced primarily by white adipose tissue under the direction of insulin, have a critical role in conferring glucose homeostasis indirectly through the central nervous system. 10,16,[35][36][37][38][39][40][41][42] The goals of this review are to collate major contributions emanating from research conducted with the aid of gene transfer technology in unraveling the neural etiology of this chronic disease of hyperglycemia, which is correctable by leptin gene therapy confined selectively to the hypothalamus, and that this neurotherapy can be gainfully employed to forestall the pathogenesis of diabetes and varied attendant comorbidities.…”