Overexpression of hypothalamic TXNIP in times of feast contributes to obesity and impaired blood glucose control.[Sebastian Kaulitzki-Fotolia.com]

Scientists in Germany have found that brain sensitivity to insulin can impact both on the degree of weight loss resulting from lifestyle intervention, and on where fat is distributed in the body. The long-term studies, carried out by researchers at the German Center for Diabetes Research (DZD), Helmholtz Zentrum München, and Tübingen University Hospital, found that if an individual’s brain responds sensitively to insulin, a significant amount of weight can be lost, unhealthy visceral fat reduced, and weight loss maintained over subsequent years. However, if the person’s brain responds only slightly or not at all to insulin, they are likely to lose relatively less weight at the beginning of the intervention, experience weight regain further down the line, and put on more visceral fat over time.

“Subjects with high insulin sensitivity in the brain benefited from the lifestyle intervention with a pronounced reduction in weight and visceral fat,” said Martin Heni, PhD, Tübingen University Hospital, who headed the study, which was reported in Nature Communications. “Even after the lifestyle intervention had ended, they only regained a small amount of fat during the nine-year follow-up.” In contrast, people with brain insulin resistance showed only a slight weight loss in the first nine months of the program. “Afterwards, their body weight and visceral fat increased again during the following months of lifestyle intervention,” added Institute for Diabetes Research first author Stephanie Kullmann, PhD. Describing their results in a paper titled, “Brain insulin sensitivity is linked to adiposity and body fat distribution,” the researchers suggested that since visceral fat is linked with diabetes, cardiovascular risk, and cancer, their findings have “implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.”

There is increasing evidence to suggest that the human brain represents an insulin-sensitive organ, and that not every brain will respond equally to insulin, the authors wrote. “A substantial number of people display an attenuated or absent insulin response, an observation often referred to as brain insulin resistance.” Studies have also shown that brain insulin plays a key role in the regulation of eating behavior and food intake, such that “brain insulin action regulates eating behavior and energy fluxes throughout the body.” What isn’t understood is how brain insulin responsiveness in humans might affect long term weight and body fat composition.

The extent to which body fat has an adverse effect on cardiometabolic health does depend on where that fat is stored. Fat accumulation in the abdomen—visceral fat—is particularly unfavorable because this type of fat releases neurotransmitters that affect blood pressure, influence the secretion of the hormone insulin, and can cause inflammation, the team continued. This increases the risk of diabetes, cardiovascular disease, and certain types of cancer. In contrast, subcutaneous fat that accumulates on the buttocks, thighs, and hips has no adverse health effects. The team points out that the health-related effects of fat distribution link to the concept of “metabolic healthy obesity,” where energy is stored primarily as subcutaneous fat, compared with “unhealthy obesity,” whereby fat accumulation is mainly in the visceral space.

What isn’t clear is why fat storage does not occur in the same place in all people. To investigate the relationship between brain insulin sensitivity, weight loss, and fat distribution, the researchers continued to analyze data from the Tübingen Lifestyle Intervention Program (TULIP), a study that had allowed the team to link brain insulin resistance to reduced weight loss during the first nine months of a two-year lifestyle intervention program. Their newly reported data have been generated through the analysis of longer-term results from the study. “We started our current analysis by testing the impact of brain insulin sensitivity on body weight and body fat distribution in the years following the 24-month lifestyle intervention.” To do this they recorded up to nine years of follow-up data for 15 participants in whom brain insulin sensitivity had been measured by magnetoencephalography before the start of the 24-month intervention.

What they found was that people with high insulin sensitivity in the brain benefitted significantly more from a lifestyle intervention that included a diet rich in fiber and exercise, than did people with insulin resistance in the brain. Not only did the individuals with higher brain insulin sensitivity lose more weight, they also had a healthier fat distribution. “Participants with high brain insulin sensitivity before entering the lifestyle intervention program achieved a greater reduction in body weight and total adipose tissue,” they reported. Baseline brain insulin sensitivity was, in addition, associated with less regain in body weight, and also with a smaller increase in total adipose tissue and visceral fat content at long-term follow-up. In contrast, brain insulin-resistant individuals showed a slight weight loss in the first nine months of the program, and these participants tended to regain body weight as well as total and visceral adipose tissue during the subsequent months of lifestyle intervention. “Even more importantly, low brain insulin sensitivity was linked to a regain in body weight and body fat in the nine years following the program,” the team wrote.

If the brain reacts sensitively to the hormone, you lose a significant amount of weight, reduce unhealthy abdominal fat, and can maintain weight in the long term. If the brain reacts only slightly or not at all to insulin, you only lose some weight at the beginning of the intervention and then gain weight again. [IDM]

Since the insulin action in the hypothalamus is crucial for the regulation of peripheral energy metabolism, the researchers also investigated how insulin sensitivity in this area of the brain is related to the distribution of body fat. To do this they looked at the results of precise functional MR imaging of hypothalamic insulin action, in a cross-sectional cohort of 112 participants. Their analysis of the data showed that people with high insulin sensitivity in the hypothalamus form little visceral fat. In contrast, insulin sensitivity had no influence on the mass of subcutaneous fat.

“Our current findings are of particular importance, given that the enlarged visceral fat content not only poses a high-risk factor for the subsequent development of diabetes, but is also robustly linked to the risk of cardiovascular disease and the development of cancer,” the researchers concluded. “Brain insulin resistance, therefore, seems to be involved in the pathogenesis of obesity in general. More importantly, it appears to be a determinant of healthy and unhealthy obesity.” And given the link between visceral fat and the increased risk of cardiovascular disease and cancer, as well as diabetes, the study results may also open up new approaches for treatment options beyond metabolic diseases.

The authors acknowledged that there were some limitations to their study. Nevertheless, Heni said, “Our study reveals a novel key mechanism that regulates fat distribution in humans. Insulin sensitivity in the brain determines where fat is deposited.” The researchers in Tübingen are already working on new therapies to abolish insulin resistance in the brain and thus have a beneficial effect on body fat distribution.

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