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.

Figures

Figure 1

Energy intake in kilocalories (kcal) from ad libitum buffet, consumed right after end of infusion and magnetic resonance imaging scan. A: All participants (n = 24); B: responders (n = 13); C: nonresponders (n = 11).

Figure 2

Hunger ratings assessed with visual analog scale (VAS) at measurement 1 + 2 (running intravenous [IV] infusion before MRI scan), 3 (right after stop of IV infusion and right after MRI scan), and 4 (right after ad libitum buffet) for responders (A; n = 13) and nonresponders (B; n = 11). 0 mm = Not at all hungry, 100 mm = very hungry. Ratings for nausea among responders (C) and nonresponders (D) are referenced by 0 mm = no nausea, 100 mm = extreme nausea. *P < 0.05.

Figure 3

Blood glucose (left) and insulin (right) concentrations for all participants (n = 24; top) and for subgroups of responders (n = 13; middle) and nonresponders (n = 11; bottom). x-Axis values indicate time after start of infusion (placebo and exenatide). At 120 min, the MRI scan was performed, lasting approximately 75 min. Right after completion of the MRI scan, the infusion was stopped and a mixed ad libitum buffet was consumed. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

Differences in eigenvector centrality between exenatide and placebo while viewing food pictures inside the MRI scanner for responders (n = 11; A) and nonresponders (n = 11; C). Bright colors signify increasing P values of paired t test between conditions. Global maximum for responders was found as depicted at Talairach coordinates −3, −1, −17 (P < 0.0001, uncorrected); cluster size was 13 voxels. No significant results were found for nonresponders. B and D show respective eigenvector centrality values for all subjects at the global maximum. Higher values signify a higher connectedness and a greater importance of the analyzed area in brain function. E: Significances of differences in eigenvector centrality exenatide condition are greater than placebo condition at the location of the hypothalamus. Corr., corrected; food, food pictures block; max, maximal; nonfood, nonfood pictures block; nonresp., nonresponders; n.s., not significant; resp., responders; uncorr., uncorrected.