Slimming Secret: Protein could inspire new weapons in battle of the bulge (Obesity)
Authors: Leslie Mitch 
Published: August 2003

A heavyweight protein might drive obese people to pile on the pounds, two independent studies report. The fat-favoring molecule apparently stymies leptin, a hormone that controls metabolism and appetite. The findings offer a new target for weight-reducing drugs and might clarify why obesity provokes diabetes and heart disease.

In principle, leptin should be every dieter's ally, because it inhibits appetite and fires up metabolism. However, leptin treatment rarely helps overweight people shed pounds. Most obese humans manufacture plenty of the molecule, but they respond feebly to it, a phenomenon called leptin resistance. With leptin a bust, scientists hope that other proteins in the same pathway will lead them to fat-burning treatments. One candidate is protein tyrosine phosphatase 1B (PTP1B). Mice lacking this protein stay trim even if they gobble a fatty diet, according to previous studies.

To explore how the protein might govern body weight, Cheng and colleagues studied mice engineered to produce no leptin. The rodents usually swell to massive size. But mice devoid of the
PTP1B
gene as well as the leptin gene gained less weight and fat and had a 30% higher metabolic rate than did mice deficient only in leptin. The researchers also found that PTP1B targets a protein called Jak2. This molecule is flipped on by the leptin receptor, a cell surface protein that binds leptin and transmits its signal into the cell. Jak2 then turns on downstream proteins.

Zabolotny and colleagues provide evidence that PTP1B prevents Jak2 from acquiring the phosphate group necessary for its activation. To accomplish this task, they slipped extra copies of the leptin receptor gene into some monkey kidney cells; others got genes for the receptor and for PTP1B. In cells given only the leptin receptor gene, Jak2 picked up a phosphate. The presence of both genes prevented Jak2 from acquiring a phosphate. From these and other experiments, both groups conclude that PTP1B reins in leptin activity by tweaking Jak2 and that blocking PTP1B might fight obesity. "It's phenomenal that two different groups arrived at the same observations," says Harvard University's Barbara Kahn, an authority on metabolism who is on the second team.

"What these two papers give us is a new candidate for resistance to leptin," says diabetes expert Roger Unger of the University of Texas Southwestern Medical Center in Dallas. By squelching the leptin signal, overactive PTP1B might deafen cells to the signal that normally makes them work harder. The results might also explain why obesity leads to diabetes and heart disease. Excess fat can poison cells in the pancreas and heart, Unger says, but leptin normally prompts cells to burn the fat before damage occurs. PTP1B might short-circuit that beneficial process. Previous studies have found increased PTP1B activity in diabetic animals.

Although the study points the way for drug developers, we still have a lot to learn about how PTP1B functions in the brain and the rest of the body, cautions endocrinologist Michael Schwartz of the University of Washington, Seattle. But if obesity boosts amounts of PTP1B, blocking the protein might get some of us back into a size 6.

--Mitch Leslie

A. Cheng, N. Uetani, P. Simoncic, V. Chaubey, A. Lee-Loy, C. McGlade, B. Kennedy, M. Tremblay, Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B.
Dev. Cell
2
, 497-503 (2002).
[Abstract]
[Full Text]

J. Zabolotny, K. Bence-Hanulec, A. Stricker-Krongrad, F. Haj, Y. Wang, Y. Minokoshi. Y.-B. Kim, J. Elmquist, L. Tartaglia, B. Kahn, B. Neel, PTP1B regulates leptin signal transduction in vivo.
Dev. Cell
2
, 489-495 (2002).
[Abstract]
[Full Text]