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Brain Insulin Resistance Linked to Overeating, Altered Homeostatic Setpoint

A new study found that in obese college students with significant visceral fat, specific brain regions became insulin-resistant.

A new study suggests that insulin resistance in particular regions of the brain that control overeating and the homeostatic setpoint are involved in visceral adiposity.

The study was published online on March 20, 2015 in Diabetes Care.

“Our results imply that insulin resistance affects not just peripheral organs but also the brain in obese young adults. However, not the entire brain is affected just particular brain regions,” commented first author Stephanie Kullmann, PhD, a postdoctoral fellow at the Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Germany.

The investigators found that obese subjects with large amounts of visceral fat were particularly vulnerable to developing insulin resistance in the hypothalamus, the homeostatic region of the brain that helps control energy balance throughout the body. The results support the theory that fat distribution, not just an elevated BMI, plays a role in metabolic health.

“Hypothalamic insulin resistance could lead to an altered homeostatic setpoint, making it particularly difficult for those individuals to lose weight,” Dr Kullmann explained.

The study also showed that peripheral insulin resistance is linked to insulin resistance of the prefrontal cortex, which plays a key role in behavioral control, including inhibitory control of eating.

“In our current study and also in previous studies, the prefrontal cortex response to insulin showed the strongest relationship with peripheral insulin resistance,” Dr Kullmann added. “Participants with peripheral insulin resistance and prefrontal insulin resistance also had difficulties with food cravings and problems with stopping eating.”

Study participants

♦ 25 lean, 10 overweight, and 13 obese students from the University of Tubingen. 

♦ Screened to rule out neurologic, psychiatric, and eating disorders, and given glucose tolerance tests to rule out diabetes. 

♦ Even though obese subjects showed evidence of peripheral insulin resistance, none had T2DM and all were considered healthy.

Study design

♦ Participants randomly received treatment on two separate days-intranasal insulin one day, placebo the next. 

♦ Fifteen to 30 minutes after participants received treatment, they underwent MRI scans to measure cerebral blood flow (CBF).

♦ They also rated desire for and liking of pictures of high-caloric savory and sweet food 60 minutes after receiving treatment.

Key results included:

♦ Hypothalamic CBF decreased significantly in all participants who received intranasal insulin vs placebo (P<.001)

♦ Level of hypothalamic response corresponded with amounts of visceral adipose tissue, independent of other fat compartments (P adjusted = .015)

♦ Only lean participants experienced insulin-induced decreases in CBF in the prefrontal cortex

♦ This prefrontal cortex response to insulin correlated negatively with peripheral insulin sensitivity (P<.001), and positively with food disinhibition (P=.004) and food craving (P=.007)

The use of intranasal insulin, which delivers the hormone directly to the brain, allowed for selective evaluation of central insulin activity. Intranasal insulin has been linked to weight loss, and improved memory and metabolism, and could be a potential therapeutic strategy for obesity, T2DM, and cognitive impairment.2 This study’s results linking hypothalamic insulin resistance with visceral adiposity and prefrontal insulin resistance with disinhibition in eating behavior, however, could suggest that intranasal insulin might not work for everyone.  

“Long-term studies are needed to show whether intranasal insulin is a treatment option for insulin resistant individuals,” Dr Kullmann concluded, “It could be that those individuals with brain insulin resistance might not benefit [from intranasal insulin].”

Take Home Points

♦♦ Research shows that insulin resistance affects not just peripheral organs but certain areas of the brain in obese university students

♦♦ Participants with large amounts of visceral fat were particularly vulnerable to developing hypothalamic insulin resistance, and may have an altered homeostatic setpoint that makes it difficult for them to lose weight

♦♦ Peripheral insulin resistance was linked to insulin resistance of the prefrontal cortex, which controls many behaviors, including inhibitory control of eating

♦♦ Participants with peripheral insulin resistance and prefrontal insulin resistance had difficulties with food cravings and control over their eating



1. Kullmann S, Heni M, Veit R, et al.  Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults.  Diabetes Care.  Published online before print March 20, 2015, doi: 10.2337/dc14-2319

2. Ott V1, Benedict C, Schultes B, et al. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab. 2012;14:214-221. doi: 10.1111/j.1463-1326.2011.01490.x. Epub 2011 Nov 16.