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Overweight and Obesity Linked with Hypothalamus Inflammation

Overweight and obese young adults have significantly larger overall hypothalamic volumes, according to a new study of structural MRI scans by researchers at the University of Cambridge. 

The team noted that while the gland was known to be an important neuroendocrine hub for the control of appetite and satiety, much of the existing evidence stems from animal studies, due to difficulties in imaging and studying the hypothalamus in vivo in humans.

Lead researcher Dr Stephanie Brown, a research fellow in the university's Department of Psychiatry, explained: "Although we know the hypothalamus is important for determining how much we eat, we actually have very little direct information about this brain region in living humans. That’s because it is very small and hard to make out on traditional MRI brain scans."

The researchers used a machine learning algorithm to analyse previously acquired structural MRI scans from four independent datasets that yielded a total of 1351 young adults across a range of body-mass index (BMI) scores. They compared hypothalamic volume, normalised to intracranial volume, in scans from individuals who were underweight, healthy weight, overweight (BMI 25 – 29.9 kg/m2, n = 55), or obese (BMI over 30 kg/m2, n = 35).

Hypothalamic Volume Larger in Overweight and Obese People

Study results, published in Neuroimage: Clinical, showed that the overall volume of the hypothalamus was significantly larger in the overweight and obese groups of young adults than in the normal or underweight groups. These volume differences were most apparent in anterior-inferior and posterior hypothalamic structures – sub-regions that control appetite through the release of hormones to balance hunger and fullness, the team said.

In addition, BMI was calculated using measured body weight and height, and a significant relationship was found between BMI and hypothalamic volume. The results have "important implications for study of the neural mechanisms of obesity in humans", according to the study authors.

High Fat Diets Linked to Hypothalamic Inflammation

The team said that animal studies had shown that both stimulation and lesions of the hypothalamus caused alterations in feeding behaviour, and consequently in body mass. Moreover, exposure to high calorie diets induced both peripheral and hypothalamic inflammation, the latter in turn prompting insulin resistance and obesity. In mice, just 3 days of a fat-rich diet is enough to cause this inflammation, they said. 

Other studies have shown that hypothalamic inflammation can raise the satiety threshold – in other words, animals have to eat more food than usual in order to feel full. Animal research thus also suggests that "hypothalamic inflammation occurs prior to weight gain, through a complex signalling cascade", the researchers said. "Alterations in hypothalamic structure and function are both a cause and a consequence of changes to food intake."

Cause and Effect Entwined in Possible Feedback Loop

For humans, it was not possible to confirm from the findings whether the structural changes were a cause or a consequence of the changes in body weight – in other words, whether increased volume in the hypothalamus in overweight and obese individuals was a result of the excess weight, or whether people with a larger hypothalamus were predisposed to eat more in the first place. 

"It is also possible that these two factors interact with each other, causing a feedback loop," they said. An inflammatory cascade of increased cytokine expression, diet-induced gliosis, blood-brain barrier disturbance, and vascular alterations may exacerbate further dysregulation of energy homeostatic mechanisms governed by the hypothalamus, they suggested, thus further challenging weight-loss strategies.

Dr Brown said: "If what we see in mice is the case in people, then eating a high-fat diet could trigger inflammation of our appetite control centre. Over time, this would change our ability to tell when we’ve eaten enough and to how our body processes blood sugar, leading us to put on weight."

The research was supported by the Bernard Wolfe Health Neuroscience Fund, the Wellcome Trust, and the NIHR Cambridge Biomedical Research Centre, with additional funding from Alzheimer’s Research UK.

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