REHOVOT, ISRAEL—May 4, 2011—Weizmann Institutescientists have added another piece to the obesity puzzle, showing howand why a certain protein that is active in a small part of the braincontributes to weight gain. This research appeared today in Cell Metabolism.
Prof. Ari Elson and his team in the Institute’s Molecular GeneticsDepartment made the discovery when working with female mice that weregenetically engineered to lack this protein, called protein tyrosinephosphatase epsilon (PTPe, for short). The scientists had originallyintended to investigate osteoporosis, and thus, they also removed theovaries of these mice. Taking out ovaries typically causes mice to gainweight to the point of obesity – so the scientists were surprised tofind that the weight of the genetically-engineered mice remained stable.Working with Dr. Alon Chen and his group in the Neurobiology Departmentand Prof. Hilla Knobler, Head of the Unit of Metabolic Disease andDiabetes of Kaplan Medical Center, the researchers fed these mice ahigh-fat diet, yet the PTPe-deficient mice maintained their sveltefigures; they burned more energy and had more stable glucose levels aswell.
To find out how the lack of this protein could keep mice slim andhealthy, the scientists looked at the hypothalamus, a region of thebrain that takes in assorted stimuli, including a wide variety ofhormones, and sends out messages of its own in the form of new hormonesand nerve signals. The hypothalamus plays a vital role in regulatingbody mass – a complex balancing act that involves, among other things,controlling appetite and physical activity.
Elson and his team found that PTPe blocks the messages from a hormonecalled leptin – a key player in body mass regulation. They revealedexactly how it does this: PTPe responds to the leptin signal in thehypothalamus, inhibiting certain molecules, which in turn dampens thatsignal.
Among its actions, leptin reduces appetite and increases physicalactivity. Paradoxically, obese people often have a surfeit of leptincirculating in their blood. This is because, while their bodies producethe hormone normally, their cells become resistant to its effects, andmore leptin is then generated to compensate.
The new research shows that PTPe plays a role in this resistance. Thescientists found that the mice lacking the protein were highlysensitive to leptin; and they remained so despite aging, ovary removalor high-fat diets. This suggests that in obese humans with leptininsensitivity, inhibiting PTPe might, conceivably, help to reestablishthe leptin response and help induce weight loss. This, however, requiresfurther research to ensure that it acts in the same way in humans withno dangerous side-effects.
Elson: “Interestingly enough, the effect seems to be gender-specific.Male mice hardly benefitted at all from the lack of PTPe compared withthe female mice. This finding could open up whole new lines of inquiryin obesity studies.”
Prof. Ari Elson’s research is supported by the M.D. MorossInstitute for Cancer Research; the Kekst Family Institute for MedicalGenetics; the Yeda-Sela Center for Basic Research; the Fritz ThyssenStiftung; the Maurice and Vivienne Wohl Charitable Foundation; and theestate of Fannie Sherr. Prof. Elson heads the Ekard Research School ofBiological Science; and the Lorry I. Lokey Research School ofBiochemical Science. He is the incumbent of the Marshall and RenetteEzralow Professorial Chair.
Dr. Alon Chen’s research is supported by the Nella and LeonBenoziyo Center for Neurosciences; the Nella and Leon Benoziyo Centerfor Neurological Diseases; the Carl and Micaela Einhorn-Dominic BrainResearch Institute; the Irwin Green Alzheimer's Research Fund; the MarkBesen and the Pratt Foundation, Australia; Roberto and Renata Ruhman,Brazil; and Martine Turcotte, Canada. Dr. Chen is the incumbent of thePhilip Harris and Gerald Ronson Career Development Chair.
