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Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.

ABSTRACT: OBJECTIVE: Glucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (reduction in energy intake after exenatide infusion) and "nonresponders." RESEARCH DESIGN AND METHODS: We performed a randomized, double-blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain. RESULTS: Responders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness. CONCLUSIONS: Our results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide-dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake.

SUBMITTER: Schlogl H

PROVIDER: S-EPMC3687323 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.

Schlögl Haiko H Kabisch Stefan S Horstmann Annette A Lohmann Gabriele G Müller Karsten K Lepsien Jöran J Busse-Voigt Franziska F Kratzsch Jürgen J Pleger Burkhard B Villringer Arno A Stumvoll Michael M

Diabetes care 20130305 7

<h4>Objective</h4>Glucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (redu ...[more]

PMID: 23462665

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Project description:ObjectiveThe hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU).ResultsOur results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide.ConclusionWe have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.

Project description:AIMS:Exenatide is a glucagon-like peptide 1 (GLP-1) mimetic which induces weight loss predominantly, it is presumed, via decreased food intake. However, circulating GLP-1 is also a determinant of energy expenditure. We sought to quantify the effect of exenatide on energy expenditure (EE) and energy intake. MATERIALS AND METHODS:In this single-center, randomized double-blind placebo controlled trial, we randomized 80 healthy, non-diabetic volunteers with obesity (46 women, age: 34.4?±?8.7?y, body fat by DXA: 44.2?±?7.8%) to subcutaneous exenatide 10??g twice daily or placebo. Subjects were admitted to our clinical research unit for measurement of 24?h-EE in a whole-room indirect calorimeter and ad libitum food intake using an automated vending machine paradigm before and after randomization. Furthermore, energy expenditure and ad libitum food intake measures were repeated at 24-week after readmission for 7-day inpatient stay. Body weight was obtained weekly for up to 5?weeks and was recorded at each monthly follow up visit up to 24?weeks. RESULTS:Prior to randomization, participants over ate during the 3-day vending machine period in the whole study group (114.6?±?35.2%), expressed as percentage of weight maintaining energy needs (WMEN) with those who were eventually randomized to exenatide overeating more (121.6?±?37.7%) compared to placebo group (107.6?±?31.5%). In the exenatide group, ad libitum absolute energy intake decreased by 1016.1?±?724.5?kcal/day (95% CI: -1250.9 to -781.2) versus a 245.1?±?710.5?kcal/day (95% CI: -475.4 to -14.7) decrease in placebo (??=?-624.8?Kcal/day, p?<?0.0001) whereas the reduction in ad libitum caloric intake relative to WMEN was a more modest 366.8?±?752.1?kcal/day (95% CI: -614.0 to -119.6) decrease compared to 8.0?±?860.1?kcal/day (95% CI: -286.8 to 270.8) reduction in placebo (??=?-382.3?Kcal/day, p?=?0.03). The decrease was uniform across all macronutrients groups. No differences in 24hEE or substrate oxidation rates were found. In the exenatide group, body weight decreased more over the 5?weeks (??=?-0.039?kg/week, p?=?0.02) and was lower compared to placebo at the end of fifth week (-1.48?±?0.77?kg; 95% CI: -3.02 to 0.05, p?=?0.06). At the 24-week follow up, there was no difference in energy intake between exenatide group and placebo group and the treatment group decreased 24-h EE more compared to placebo (??=?-160.6?Kcal/day, 95% CI: -307.6 to 13.6, p?=?0.03) compared to their pre-randomization measurement. However, this reduction was not present after adjustment for changes in FM and FFM (??=?-87?kcal/day, p?=?0.14). No difference was observed in body weight (??=?-1.72?kg, 95% CI: -5.77 to 2.30, p?=?0.39) in exenatide versus placebo over 24?weeks. CONCLUSION:Compared with placebo, exenatide decreased early ad libitum energy intake but did not change 24?h-EE. However, the reduction was more modest in relative versus absolute terms (i.e. below that needed for WMEN). Thus, although rate of weight change was greater in the exenatide treated subjects at 5?weeks, the absolute difference in weight was not significant. These findings indicate that although exenatide reduces food intake, it may be more beneficial in blunting overeating and thus may serve to more prevent weight regain following initial weight loss.

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Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.

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Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.

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