Obesity is reaching epidemic levels in some parts of the world, and scientists are teasing apart the details to understand why it is such a persistent condition. A study in the Journal of Biological Chemistry adds substantially to the story by the discovery of a molecular chain of events in the brains of obese rats that undermined their ability to suppress appetite and to increase energy expenditure.
It's a vicious spiral, involving a breakdown in how brain cells process key proteins that allows obesity to promote further obesity. But researchers at Brown University found that they could intervene to break that cycle by fixing the core protein-processing problem.
We already know one mechanism in which obesity perpetuates itself by causing resistance to leptin; a hormone that signals the brain about the status of fat in the body. However years ago senior author Eduardo A. Nillni, professor of medicine at Brown University and a researcher at Rhode Island Hospital, observed that after meals obese rats had a scarcity of another key hormone—alpha-melanocyte stimulating hormone (a-MSH)—compared to rats of normal weight.
Alpha-MSH has two jobs in parts of the hypothalamus region of the brain. One is to suppress the activity of food-seeking brain cells. The second is to signal other brain cells to produce the hormone Thyrotropin-releasing hormone (TRH), which prompts the thyroid gland to increase energy expenditure in the body. In the obese rats alpha-MSH was low, despite an abundance of leptin and despite normal levels of a very important protein called pro-opiomelanocortin (POMC), which is a precursor to many vital chemicals in the body, including a-MSH.
Since there was sufficient raw material for a-MSH production and the enzymes for conversion were in place, the researchers then smartly looked upstream of the process to see where, if any, a limiting step occurred.
The research team fed one group of rats a high-energy dense diet and fed others a normal diet for 12 weeks. The overfed rats developed the condition of ‘diet-induced obesity.’ The team then studied the hormone levels and brain cell physiology of the rats. They also tested their findings by experimenting with the biochemistry of key individual cells in-vitro. They found that in the obese rats the endoplasmic reticulum (ER), which is the part of your cells that build your proteins, becomes stressed and overwhelmed. The overloaded ER then failed to properly handle Prohormone Convertase 2 (PC2), which is a key enzyme in the synthesis of a-MSH.
The PC2 levels they measured in obese rats, for example, were 53 percent lower than in normal rats. Alpha-MSH peptides were also barely more than half as abundant in obese rats as they were in healthy rats.
To confirm the findings, the researchers tested this concept further. In additional experiments the researchers purposely induced stress in the ER of a group of rats and found that there was a decrease in both PC2 and a-MSH. They also treated lean and obese rats for two days with a chemical called Tauroursodeoxycholic acid (TUDCA), which is known to alleviate ER stress. If ER stress was responsible for alpha-MSH production problems, the researchers would see alpha-MSH recover in obese rats treated with TUDCA. While TUDCA didn't increase alpha-MSH production in normal rats, it increased it markedly in the obese rats.
The researchers also isolated neurons that produce PC2 and POMC and pre-treated some with a similar chemical called 4-phenyl butyric acid (PBA) that prevents ER stress. They left others untreated. They then induced ER stress in all the cells. Under that ER stress, those that had been pre-treated with PBA produced about twice as much PC2 as those that had not.
The authors concluded that there is a direct link between obesity and ER stress resulting in altered POMC processing, which brings a new perspective of how ER stress can regulate energy balance by altering POMC processing.
There are many factors that are linked to ER stress, here are just a few: Glucose deprivation, Calcium homeostasis disturbance, Hypoxia, Elevated homocysteine, Pro-inflammatory mediators, ATP depletion, Excess Nitric Oxide, Alcohol metabolism, Lp(a) cholesterol, Oxidised lipids, Oxidative stress, and Insulin resistance.
Although this curtailed list still seems like a lot of ground to cover, it’s actually really not. You can cover all of those bases with a handful of relatively effortless lifestyle modifications. And to really up the ante, if I’m correct, you may be able to replicate the chemical intervention with a simple addition to your meals which ties neatly into another groundbreaking study from a few months back. Interesting times.
Reference:
Isin Cakir, Nicole E. Cyr, Mario Perello, Bogdan Patedakis Litvinov, Amparo Romero, Ronald C. Stuart, and Eduardo A. Nillni. Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing. J. Biol. Chem. jbc.M113.475343. First Published on May 2, 2013, doi:10.1074/jbc.M113.475343
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