Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

Abstract

Background GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. Basic Procedures Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17 days (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days) of treatment, we also studied changes in fMRI responses to food cues. Main Findings By design, to avoid any confounding by weight changes, subjects were studied for 17 days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. Principal Conclusions We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that would over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

Longer‐term liraglutide administration at the highest dose approved for obesity increases reward‐related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti‐obesity therapies

“…Participants viewed food and non‐food cues within a 3‐Tesla GE MR750 scanner at BIDMC while fasting, using a GE 32‐channel head array coil with a protocol similar to our previous publications . First, a T1‐weighted Magnetization Prepared Rapid Gradient Echo (MPRAGE) structural MR image was acquired.…”

“…Participants viewed food and non-food cues within a 3-Tesla GE MR750 scanner at BIDMC while fasting, using a GE 32-channel head array coil with a protocol similar to our previous publications. 11,[14][15][16][17][18] Figure S1). Weight, BMI, waist circumference and fasting glucose were decreased and cholesterol levels improved while using liraglutide (Table 1).…”

Exendin-4 disrupts responding to reward predictive incentive cues in rats

“…Further supporting this hypothesis, in diabetic humans GLP-1R agonists have been shown to decrease neuronal activation induced by food cues (e.g. pictures of palatable food) (Farr et al, 2016;Ten Kulve et al, 2016). In rodent models, central administration of EX4 attenuates cue-induced reinstatement of sucrose seeking and conditioned place preference for a high-fat food (Ong et al, 2017).…”

Research advances in metabolism 2016

“…Farr et al [99] enrolled 20 patients with T2DM in a randomized, placebo-controlled, cross-over trial who were studied after placebo and liraglutide for 17 days (3 days at 1.8 mg) and before weight loss. While on liraglutide, participants showed approximately a 10% decrease in fasting leptin levels (p < .01) and a 53% increase in GIP (p < .03).…”