As Fat as You Want to Be

Popular culture teaches us that obesity is an illness, the obese are victims, and the victims have no control over their disease. Is this Opra-esque parcel of victimology accurate?

Snowcrash from Biosingularity blog reports on research from the Salk Institute that delves deeply into the physiological mechanisms of fat storage, metabolism, and synthesis. Some of the results are amazing.

The engineered mice consumed an equally high-fat diet but did not gain weight, indicating that fat storage pathways can be tweaked. "Maybe the most amazing finding is that these mice are protected from fatty liver disease, a serious problem in obese individuals with insulin resistance," says Montminy.

Our body's ability to store fat requires the activity of the enzyme acetyl-coenzyme A carboxylase, or ACC. When we fast, the body starts to burn fat while simultaneously shutting down ACC through a chemical modification called phosphorylation.

The Salk researchers found that a critical protein called TRB3 orchestrates a second chemical modification of ACC, known as ubiquitination, which gets rid of the enzyme altogether. "In this parallel pathway, TRB3 serves as a go-between for an enzyme that marks ACC for degradation," says Jose Heredia, a graduate student in Montminy's lab.

TRB3 levels in adipose tissue usually rise only during fasting, when ACC should be turned off. Heredia and co-first author Ling Qi, Ph.D., reasoned that keeping the TRB3 pathway artificially "on" during both fasting and feeding might melt away fat depots.And that's exactly what happened. Mice genetically engineered to express permanently elevated levels of TRB3 protein in fat tissue were 10-20 percent skinnier than normal mice. "Even when we put them on a high-fat diet, these mice just didn't gain any weight," says Qi. "Their physical activity was the same, but they were constantly burning fat."

All this is good news for the fight against obesity and the disorders characterized by insulin-resistance known as "metabolic syndrome." Most people with insulin resistance will develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight–about 10 to 15 pounds for someone weighing 200 pounds. Defining how molecules regulating fat storage interact could lead to novel measures to curb obesity.

Further evidence linking TRB3 to disease comes from recent findings from a team of Italian scientists who report that mutations in the human TRB3 gene are associated with several insulin resistance-related health problems, such as high insulin levels, high cholesterol, and cardiovascular disease. Source.

This would be particularly good news for persons with type 2 diabetes--insulin resistance. These persons are almost always obese, and additionally suffer all the health risks of diabetics--atherosclerosis, neuropathies, small blood vessel occlusions, renal disease, loss of vision, ASHD, and early mortality. Clearly these unfortunate people do not want to suffer all that morbidity. Just as clearly, physicians are growing tired of dealing with these cookie cutter patients, many of whose very real medical problems are lifestyle choice induced.

And honestly, we all know people who hide behind their obesity like a shield. Their obesity allows them to avoid situations that might be uncomfortable for them. Likewise we all probably know relatively physically fit spouses who are comfortable with the obesity of their spouse. Or physically fit parents who are comfortable with the obesity of their child. There is indeed a significant amount of secondary gain involved for many obese people, and obesity enablers.

Scientists are determined to make obesity a matter of choice. Not all of the obese are necessarily appreciative. Certainly an effective medical cure will relieve many people of the near-impossible amount of physical work and self-discipline that would be required for them to lose weight without drugs. But what about the psychological motivations to remain obese?

The psychological underpinnings of many persons' obesity may be the most difficult thing to cure, in the end. Society will try to make that psychology a disease, and scientists will continue developing drugs for all symptoms and discomforts--physical and psychological.