Abstract
Catecholamine excess reflecting an adrenergic overdrive of the sympathetic nervous system (SNS) has been proposed to link to hyperleptinemia in obesity and may contribute to the development of metabolic disorders. However, relationship between the catecholamine level and plasma leptin in obesity has not yet been investigated. Moreover, whether pharmacological blockade of the adrenergic overdrive in obesity by the third-generation beta-blocker agents such as carvedilol could help to prevent metabolic disorders is controversial and remains to be determined. Using the high fat diet (HFD)-induced obese mouse model, we found that basal plasma norepinephrine, the principal catecholamine as an index of SNS activity, was persistently elevated and highly correlated with plasma leptin concentration during obesity development. Targeting the adrenergic overdrive from this chronic norepinephrine excess in HFD-induced obesity with carvedilol, a third-generation beta-blocker with vasodilating action, blunted the HFD-induced hepatic glucose over-production by suppressing the induction of gluconeogenic enzymes, and enhanced the muscular insulin signaling pathway. Furthermore, carvedilol treatment in HFD-induced obese mice decreased the enlargement of white adipose tissue and improved the glucose tolerance and insulin sensitivity without affecting body weight and blood glucose levels. Our results suggested that catecholamine excess in obesity might directly link to the hyperleptinemic condition and the therapeutic targeting of chronic adrenergic overdrive in obesity with carvedilol might be helpful to attenuate obesity-related metabolic disorders.
Highlights
Obesity and related adverse consequences such as metabolic disorders and cardiovascular diseases (CVDs) have become a global health problem in modern society [1]
These results suggested that basal norepinephrine was persistently elevated during high fat diet (HFD)-induced obesity development and highly correlated with plasma leptin, but not plasma insulin
Unlike the results observed in livers and muscles of the carvedilol-treated mice, we found that carvedilol failed to suppress the HFD-induced increase of p-Creb levels in the brown adipose tissues (BAT) of HFD-fed mice (S2A and S2B Fig)
Summary
Obesity and related adverse consequences such as metabolic disorders and cardiovascular diseases (CVDs) have become a global health problem in modern society [1]. Overactivation of the sympathetic nervous system (SNS) which has been well-documented in obesity [2] plays an important role in the pathogenesis of obesity-associated CVDs [3, 4] and may contribute to the development of metabolic disorders in obesity [5,6,7]. Catecholamine excess which leads to adrenergic receptor overactivation is known to cause profoundly adverse effects on metabolism and cardiovascular function as seen in patients with pheochromocytoma [25, 26]. Whether catecholamine excess is observed in obesity and links to hyperleptinemia has not yet been investigated It remains controversial whether targeting the SNS hyperactivity in obesity by pharmacological treatment could help to prevent metabolic disorders [6]
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