Abstract
Background:The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation.Objectives:We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet.Materials/Methods:We continuously administered liraglutide either intrahypothalamically (10 μg per day) or subcutaneously (200 μg kg−1 per day) for 28 days to lean Sprague Dawley rats (n=8 each). We assessed changes in body weight, adipose tissue mass, adipocyte size and adipose tissue volume in the abdominal region by using micro-CT. We analyzed genetic expression patterns of browning, thermogenic and adipocyte differentiation regulators in adipose tissues as well as particular neuronal appetite regulators in the hypothalamus.Results:Intrahypothalamic liraglutide administration induced an 8% body weight reduction at day 9 compared with the control group (P<0.01) and a 7% body weight loss at day 9 compared with subcutaneous liraglutide treatment (P<0.01), supported by a significant reduction in adipose tissue mass and volume with intrahypothalamic liraglutide administration (P<0.05). Our data show that chronic intrahypothalamic liraglutide treatment triggered an 18-fold induction of the hypothalamic mc4r gene (P<0.01) accompanied by a significant increase in circulating thyroxine (T4) levels (P<0.05).Conclusions:Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis.
Highlights
Liraglutide is a long-acting GLP-1 receptor (GLP-1R) agonist and has been FDA and EMA approved for the treatment of obesity.[1]Liraglutide lowers blood glucose levels by stimulating insulin secretion and by inhibiting glucagon secretion in a glucosedependent manner.[2]
Central chronic liraglutide treatment reduces body weight gain and promotes adipose tissue mass reduction Intrahypothalamic treatment resulted in a significant body weight loss of 4% at day 7 (P o0.05) and 5% at day 9 (P o 0.05) compared with baseline
Intrahypothalamic liraglutide treatment resulted in a significant reduction of inguinal white and interscapular brown adipose tissue compared with subcutaneous liraglutide treatment (P o 0.01; Figure 1f)
Summary
Liraglutide is a long-acting GLP-1 receptor (GLP-1R) agonist and has been FDA and EMA approved for the treatment of obesity.[1]Liraglutide lowers blood glucose levels by stimulating insulin secretion and by inhibiting glucagon secretion in a glucosedependent manner.[2]. Body weight loss was attributed to the stimulation of thermogenesis in the brown adipose tissue (BAT) and browning of white adipose tissue (WAT) via the hypothalamic AMP-activated protein kinase pathway.[5] Peripheral liraglutide administration led to a reduced ability to suppress food intake and maintain body weight in dietinduced obese mice with a GLP-1 receptor knockdown in the central nervous system.[6] In addition, peripheral liraglutide administration in rats with pharmacological antagonized GLP-1 receptors in the brain resulted in a reduced ability to suppress food intake.[7] A recent study identified POMC/ CART neurons in the arcuate nucleus of the hypothalamus as the main mediators of weight-reducing effects after chronic peripheral liraglutide treatment.[8] But peripheral administration of liraglutide often leads to only limited effects mediated in the brain because only small amounts of the large liraglutide–albumin complex can cross the blood–brain barrier.[4] In humans, such a limited passive transport of peripherally administered liraglutide to the cerebrospinal fluid did not correlate with the observed weight loss.[9]. CONCLUSIONS: Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis
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