Why obese have problem losing weight

Teresa Tanoos's picture
Researchers discover why obese have problem losing weight.
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Researchers report a new discovery of a complex set of neurochemical processes that show obesity can sustain itself, undermining hormones that would otherwise curb appetite or increase the rate at which calories are burned.

The discovery, made by Brown University researchers while studying the brain cells of obese rats, is published in the Journal of Biological Chemistry.

At the root of the problem is a breakdown in the brain’s ability to process key proteins. This, in turn, promotes a vicious cycle that allows obesity to beget further obesity. However, researchers also found that they could intervene to break the cycle by fixing the core protein-processing problem, so the new discovery could prove encouraging over the long run.

Prior to the study, scientists were already aware that one way obesity perpetuates itself is by causing resistance to leptin, a hormone that signals the brain about the status of fat in the body.

However, senior author Eduardo A. Nillni, professor of medicine at Brown University and a researcher at Rhode Island Hospital, observed years ago in obese rats after meals, that they were deficient in another key hormone, alpha-MSH, compared to rats of normal weight.

"This is so novel. Nobody ever looked at that," said Nillni.

So what does Alpha-MSH do? Essentially it has two functions within parts of the hypothalamus region of the brain. One function is to suppress the activity of food-seeking brain cells, and the second is to signal other brain cells to produce the hormone TRH, which prompts the thyroid gland to stimulate calorie burning activity in the body.

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For the study, Nillni and his colleagues conducted research to find out where the alpha-MSH deficit in obese rats was coming from, as Nillni said he suspected the problem might lie in the brain cells' mechanism for processing the POMC protein to make alpha-MSH.

Over a period of 12 weeks, the research team fed some rats a high-calorie diet while they fed other rats a normal diet. As a result, the overfed rats developed a condition called "diet-induced obesity." Next, the research team studied the hormone levels and brain cell physiology of the rats and also tested their findings by experimenting with the biochemistry of key individual cells on the lab bench.

Their findings revealed that in the obese rats, a key "machine" in the protein-making process of the brain became stressed and overwhelmed, leading to the an overloaded “machine” that thwarted the process from efficiently managing the chain of events that occurs in the brain cells of normal weight rats. Indeed, levels of Alpha-MSH in obese rats were less than half what they were in their slender counterparts.

Nillni cautioned that although his team found ways to fix the protein-making process at the root of the problem, the agents used in the study are not readily applicable as medicines for treating obesity in humans – and there could be unknown and unwanted side effects, which are not approved for human use by the Food and Drug Administration.

Nevertheless, Nillni explained that by laying out the exact mechanism responsible for why the brains of the obese rats failed to curb appetite or spur greater calorie burning, the study reveals several opportunities to drug manufacturers where they can intervene to break this new, vicious cycle that causes obesity to perpetuate itself.

"Understanding the central control of energy-regulating neuropeptides during diet-induced obesity is important for the identification of therapeutic targets to prevent and or mitigate obesity pathology," the authors wrote.

To learn more about obesity and the brain, click here.

SOURCE: Journal of Biological Chemistry. Vicious cycle: Obesity sustained by changes in brain biochemistry; Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing, First Published on May 2, 2013, doi:10.1074/jbc.M113.475343

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