Brain Activation in Response to Low-Calorie Food Pictures: An Explorative Analysis of a Randomized Trial With Dapagliflozin and Exenatide

Abstract

Background and AimSodium-glucose cotransporter-2 inhibitors (SGLT2i) induce less weight loss than expected. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, contributing to increased appetite and food intake. This hyperphagia may be specific to high-calorie foods. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with lower preferences for high-calorie foods, and with decreased activation in areas regulating satiety and reward in response to high-calorie food pictures, which may reflect this lower preference for energy-dense foods. To optimize treatment, we need a better understanding of how intake is controlled, and how [(un)healthy] food choices are made. The aim of the study was to investigate the effects of dapagliflozin, exenatide, and their combination on brain activation in response to low-calorie food pictures.MethodsWe performed an exploratory analysis of a larger, 16-week, double-blind, randomized, placebo-controlled trial. Sixty-eight subjects with obesity and type 2 diabetes were randomized to dapagliflozin, exenatide, dapagliflozin plus exenatide, or double placebo. Using functional MRI, the effects of treatments on brain responses to low-calorie food pictures were assessed after 10 days and 16 weeks.ResultsDapagliflozin versus placebo decreased activity in response to low-calorie food pictures, in the caudate nucleus, insula, and amygdala after 10 days, and in the insula after 16 weeks. Exenatide versus placebo increased activation in the putamen in response to low-calorie food pictures after 10 days, but not after 16 weeks. Dapagliflozin plus exenatide versus placebo had no effect on brain responses, but after 10 days dapagliflozin plus exenatide versus dapagliflozin increased activity in the insula and amygdala in response to low-calorie food pictures.ConclusionDapagliflozin decreased activation in response to low-calorie food pictures, which may reflect a specific decreased preference for low-calorie foods, in combination with the previously found increased activation in response to high-calorie foods, which may reflect a specific preference for high-calorie foods, and may hamper SGLT2i-induced weight loss. Exenatide treatment increased activation in response to low-calorie foods. Combination treatment may lead to more favorable brain responses to low-calorie food cues, as we observed that the dapagliflozin-induced decreased response to low-calorie food pictures had disappeared.

Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions

“…Further, intranasal neuropeptide oxytocin (OXT), which is a nine-amino acid neuropeptide hormone predominantly synthesized in the paraventricular and supraoptic nuclei of the hypothalamus that decreases food intake and body weight in animal models, had the following effects: (1) reduced food craving during a cognitive control task; (2) reduced functional connectivity between VTA and insula/SMA/AMY/HIPP/MTG during viewing high-calorie food cues; and (3) increased activation in MFG, SFG, precuneus and cingulate cortex to high-calorie food cues [ 124 , 224 ]. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, decreased food cue-related activation in the caudate, insula, AMY after 10 days treatment and in the insula after 16 weeks, whereas exenatide, a GLP-1RA, increased activation in the putamen only after 10 days, and dapagliflozin plus exenatide relative to dapagliflozin only increased activation in the insula and AMY to low-calorie food cues [ 225 ]. Finally, bupropion when combined with naltrexone decreased resting-state activity in the MFG and SPG, and increased functional connectivity of SPG-dACC/insula, and decreased functional connectivity of SPG-IFG [ 122 ].…”

Review of upcoming and currently available anti-obesity drugs in Europe

“…Although in monotherapy flozins to some extent promote weight loss, the effect is hard to maintain due to compensatory mechanisms, such as secondary increase of caloric intake promoted by renal loss of glucose. [54] Mentioned before GLP-1 analogues increase satiety and lessen high-calorie food craving therefore, to some extent, they potentialize SGLT2i-promoted weight loss while having their own beneficial effect. [55] Randomized placebo controlled studies in overweight and obese patients with no coexisting diabetes (oral dapagliflozin 10 mg daily and subcutaneous exenatide 2 mg weekly) conducted in 2016 with follow-up study in 2017 showed sustained mean weight loss (-4.5kg at 24 weeks vs placebo, -5.7kg at 52 weeks vs placebo) with predominantly adipose tissue loss without changes in lean body mass (Table 6.).…”