Role of autonomic nervous system in chronic CNS-mediated antidiabetic action of leptin

Abstract

This study tested whether ganglionic blockade or hepatic vagotomy attenuates the chronic central nervous system (CNS)-mediated antidiabetic and cardiovascular effects of leptin. Male Sprague-Dawley rats were instrumented with telemetry probes and arterial and venous catheters for determination of blood pressure (BP), heart rate (HR), blood sampling, and intravenous (iv) infusions. An intracerebroventricular (ICV) cannula was placed into the brain lateral ventricle for infusion of leptin or vehicle. After control measurements, streptozotocin (STZ) was injected iv (50 mg/kg) to induce diabetes, and 5 days later leptin ( = 6) or saline vehicle ( = 5) was infused ICV for 12 days via osmotic pumps. Beginning on of leptin treatment, the ganglionic blocker hexamethonium (15 mg·kg·day iv) was infused, while leptin infusion was continued, to assess the role of the autonomic nervous system. Induction of diabetes was associated with increases in blood glucose (98 ± 7 to 350 ± 19 mg/dl), food intake (23 ± 3 to 43 ± 3 g/day), decreases in HR (-70 ± 11 beats/min), polyuria, and increased water consumption, which were all completely normalized by ICV leptin infusion. Although hexamethonium attenuated leptin's effect on HR, it failed to impair leptin's ability to restore euglycemia or to prevent the polyuria or increased water intake in STZ-diabetic rats. We also found that after pretreatment with hexamethonium ( = 8), ICV leptin infusion, during continued ganglionic blockade, completely normalized blood glucose in diabetic rats. In addition, selective hepatic vagotomy did not attenuate leptin's ability to restore euglycemia in diabetic rats. These results suggest that leptin's powerful chronic CNS antidiabetic actions are mediated primarily via nonautonomic mechanisms.

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences

“… 8 , 49 However, activation of the autonomic nervous system cannot fully explain leptin's effects on metabolism in peripheral tissues, including the heart. 5 , 6 Our results corroborate these previous studies examining the chronic effects of leptin on glucose regulation, and suggest that leptin's CNS cardioprotective effects that improve mitochondrial function and myocardial contractility in hearts after I/R injury are not mediated primarily by the sympathetic nervous system. Using parabiosis, we recently provided evidence that the CNS‐mediated antidiabetic effects of leptin may involve release of a brain‐derived factor that circulates in the blood and produces a powerful glucose‐lowering effect.…”

“…Previous studies from our laboratory and from others showed that leptin increases sympathetic activity to peripheral tissues including the heart. 5 , 6 , 7 , 8 Although some studies suggest that increased sympathetic activation to the heart may be detrimental in HF, 9 cardiac sympathetic innervation is an important compensatory mechanism for increasing cardiac function in situations of stress, such as during MI. 10 However, the role of the cardiac nerves in mediating the chronic effects of leptin on cardiac function after I/R injury have not, to our knowledge, been previously reported.…”

Leptin Receptors in RIP-Cre25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice

“…As we mentioned above, HPA-axis and the SNS contribute to hypothalamic regulation of lipid metabolism by leptin in the presence of insulin. Studies have shown that leptin can restore normal glycemia in the absence of insulin while HPA-axis or the SNS is removed from the system (61,62,67,68), implicating that they are not required for lipid-lowering effects of leptin in an insulin-independent manner. Further studies are needed to decipher the factor which connects the hypothalamus to peripheral tissues to mediate lipid-lowering effects of leptin in an insulin-independent manner.…”

Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system actions

“…In contrast to these acute studies, we previously showed that chronic blockade of α 1 , β 1 , β 2 and β 3 adrenergic receptors did not attenuate leptin’s ability to restore euglycemia in STZ-diabetic rats [ 5 ]. We also demonstrated that neither ganglionic blockade nor hepatic vagal denervation substantially attenuated the chronic CNS-mediated antidiabetic effects of leptin [ 21 ]. Thus, although the ANS may play an important role in mediating the acute effects of leptin on glucose regulation, the chronic CNS-mediated antidiabetic effects of leptin appear to be through other mechanisms.…”