Objective To utilize quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. Methods Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N=22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N=23) from the lowest tertile. In a separate postmortem study, brain slices (N=10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). Results In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P=0.01). Compared to controls, cases had longer T2 relaxation times in the right MBH (P<0.05), as well as higher BMI (P<0.05), fasting insulin concentrations (P<0.01), and HOMA-IR values (P<0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P<0.05), validating an MRI-based method for the detection of MBH gliosis in humans. Conclusions These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.

Postmeal satiety is shown in regional brain activation by images of high-calorie foods. Regions including the amygdala, nucleus accumbens, and dorsal striatum may alter perception of, and reduce motivation to consume, energy-rich foods, ultimately driving food choice. This trial was registered at clinicaltrials.gov as NCT01631045.

The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.

Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663.

Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, 8 normal weight participants (7 men, BMI 19–24.7 kg/m2, age 19–29 yr) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9–39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600–750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 minutes later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 −62±5 Placebo −41±9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.