Research Briefs

NIDDK, NHLBI, ORS, NCI, NIAID: Potential to Curb Obesity and Type 2 Diabetes

An NIH-led team of scientists may have found a new way to burn calories. They have uncovered a pathway in mice that allows white fat—a contributor to obesity and type 2 diabetes—to burn calories in the same way that brown fat and muscle do. Changing white fat into brown fat or muscle is a potential new approach to treating obesity and type 2 diabetes, although the research is a long way from being applicable to people.

The researchers made their discovery by reducing the actions of a protein called transforming growth factor (TGF)–beta in two ways: through genetic engineering and by using an antibody that finds and blocks the TGF-beta protein. TGF-beta proteins determine the capacity of cells to grow and function normally. When the actions of TGF-beta were suppressed, the researchers saw that the mice's white fat got browner and had more mitochondria. The increased metabolic activity due to the extra mitochondria led to the mice burning more calories, thus lessening obesity.

The TGF-beta–blocking antibody is also being tested as a cancer treatment in people in a trial at NCI. The researchers next plan to design a more targeted approach to partially transform white fat of mice into brown fat or into a muscle-like state without compromising the immune system. (NIH authors: H. Yadav, C. Quijano, A.K. Kamaraju, O. Gavrilova, R. Malek, W. Chen, P. Zerfas, D. Zhigang, E.C. Wright, C. Stuelten, P. Sun, M., A.E. Sumner, T. Finkel, S G. Rane; Cell Metab 14:67–79, 2011)

NIDDK: Findings Challenge One-Size-Fits-All Weight Assumptions

Why do some people lose weight faster or slower than others even when they eat the same food and get the same amount of exercise? NIDDK researchers joined with scientists from the World Health Organization and other institutions to create a mathematical model—and an accompanying online weight-simulation tool—of what happens when people of varying weights, diets, and exercise habits try to change their weight. The findings challenge the commonly held belief that eating 3,500 fewer calories—or burning them off exercising—will always result in a pound of weight loss.

Instead, the computer simulations indicate that this assumption overestimates weight loss because it fails to account for how metabolism changes. The researchers hope to use the knowledge gained from developing the model and from clinical trials to design personalized weight-management programs.

The online simulation tool simulates how factors such as diet and exercise can alter metabolism over time and thereby lead to changes of weight and body fat. (NIDDK authors: K. Hall, C. Chow, D. Chandramohan; Lancet 378:826–847, 2011)

NHLBI, NINDS, CC: Protein Linked to Parkinson Disease May Regulate Fat Metabolism

A defective protein may indirectly contribute to the development of some early-onset Parkinson disease by changing the amount and types of fat in people’s bodies. In a preliminary study, NHLBI and NINDS researchers have found that Parkin, a protein linked with some cases of early-onset Parkinson disease, regulates how cells take up and process dietary fats. Mutations in the gene for Parkin are present in as many as 37 percent of early-onset Parkinson cases. However, laboratory mice with defective Parkin do not display obvious signs of the disease and did not gain weight in response to a high-fat laboratory diet, as regular mice typically do.

The researchers saw a similar pattern when they analyzed blood cells from patients enrolled at the NIH Parkinson Clinic. In lab tests, cells from people with the defective gene for Parkin had less ability to absorb fat. These results provide evidence that the findings could be relevant in humans.

The researchers plan some early-stage clinical studies on the connection between fat metabolism and Parkinson disease. (NIH authors: K. Kim, M.V. Stevens, M.H. Akter, S.E. Rusk, R.J. Huang, A. Cohen, A. Noguchi, D. Springer, A.V. Bocharov, T.L. Eggerman, D. Suen, R.J. Youle, M. Amar, A.T. Remaley, M. Sack; J Clin Invest DOI: 10.1172/JCI44736)

NIDA: Potential New Target for the Treatment of ADHD

The most common treatment for attention-deficit hyperactivity disorder (ADHD) is to administer psychostimulant medications. It is unclear how these compounds work. NIDA researchers who were part of a multinational collaborative determined that a specific receptor subtype in the brain could play a role in the risk for ADHD. The findings may help explain how stimulants work to treat its symptoms.

Dysfunction of the dopamine D4 receptor subtype is linked to ADHD as well as to other disorders characterized by decreased impulse control, including drug abuse. One subtype variant, D4.7, has been of particular interest because of its increased prevalence in those diagnosed with ADHD. The researchers inserted three variants of the dopamine D4 receptor into cells and into mice and found that the D4.7 variant, unlike its D4.2 and D4.4 counterparts, was not able to interact with the short version of the dopamine type 2 (D2S) receptor to reduce glutamate release in a brain region associated with impulsivity and symptoms of ADHD in humans. The results suggest that psychostimulants might reduce glutamate release by amplifying this D4-D2S interaction, and this amplification might explain why these medications are less efficient in patients with the D4.7 variant. (NIDA authors: S. Ferre, D. Volkow, J. Borycz; Mol Psychiatry DOI: 10.1038/mp.2011.93)