New key brain target of fat hormone

January 18, 2006

Researchers have identified a new area of the brain that responds to the fat hormone leptin in regulating body weight and energy expenditure. They said that the region seems to be particularly important in enabling the body to resist weight gain from a high-fat diet. Their discovery, they said, indicates that leptin acts on more brain areas than previously believed, to regulate body weight.

Leptin is secreted by fat tissue into the bloodstream, where it travels to the brain and other tissues. It acts on leptin receptors in areas of the hypothalamus to trigger fat loss and decreased appetite.

Bradford Lowell and his colleagues published their findings in mice in the January 19, 2006, issue of Neuron. They reported that an area called the ventromedial hypothalamus (VMH) is also important in leptin response, in addition to the area called the arcuate nucleus (ARC) of the hypothalamus, which is already known to be a target of leptin signaling.

Even though leptin was known to act on the neurons of the ARC, wrote the researchers, knocking out leptin receptors in those neurons caused only mild obesity in mice, compared to the effects of knocking out such receptors throughout the brain. Such findings, they said, hinted at the role of another region of the hypothalamus as a leptin target. The VMH constituted a good candidate for such a leptin target region because neurons there express leptin receptors, said the researchers. Also, they noted, destroying the VMH produces massive obesity in mice.

To explore the role of the VMH in leptin signaling, Lowell and his colleagues generated mice lacking leptin receptors only in specific neurons in the VMH. Electrophysiological studies of the VMH neurons in these altered mice showed that they were not triggered by leptin to fire, as were such neurons in normal mice.

The researchers found that the mice lacking VMH leptin receptors showed the same degree of body weight gain as those engineered to lack leptin receptors in the ARC. What's more, the researchers found that knocking out both types of neurons showed an additive effect on weight gain in the animals. Their measurements in the mice revealed that such weight gain was due to an increase in fat stores.

Importantly, when the researchers fed the mice deficient in VMH leptin receptors a high-fat, high-sugar diet, they found that the animals rapidly gained weight throughout the feeding period. In contrast, normal mice gained some weight, but leveled off during the feeding period. The knockout mice continued to gain weight, found the researchers, because they did not suppress their food intake, as did normal mice.

The researchers noted that the combined effects on obesity of the deficiency of VMH leptin receptors and high-fat feeding "were greater than expected from the individual components added together.

"This synergistic interaction strongly suggests that leptin action on [the VMH neurons] plays a particularly important role in resisting high-fat-diet-induced obesity."

Lowell and his colleagues concluded that "In total, these findings suggest that the ability of leptin to restrain body weight is distributed to a number of different sites in the brain."
-end-
The researchers include Harveen Dhillon, Jeffrey M. Zigman, Chianping Ye, Charlotte E. Lee, Robert A. McGovern, Vinsee Tang, Christopher D. Kenny, Lauryn M. Christiansen, Ryan D. White, Elisabeth A. Edelstein, Roberto Coppari, Nina Balthasar, Joel K. Elmquist, and Bradford B. Lowell of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, MA; Michael A. Cowley of Oregon Health and Science University in Portland, OR; Streamson Chua Jr. of Albert Einstein College of Medicine in New York, NY. This work was supported by grants from the National Institutes of Health (PO1 DK56116 to B.B.L. and J.K.E., MH61583 and DK53301 to J.K.E., and R01 DK53301-07S2 to B.B.L, J.K.E., and M.A.C.) and by Takeda Pharmaceutical Company, Ltd.,Japan. H.D. was supported by an American Heart Association fellowship and a Boston Obesity Nutrition Research Center Pilot Project Award; N.B. was supported by The Wellcome Trust, UK, an EASD-ADA, and a Boston Obesity Nutrition Research Center award. J.M.Z. was supported grants from the National Institutes of Health (1F32DK64564-01 and 5T32DK07516).

Dhillon et al.: "Leptin Directly Activates SF1 Neurons in the Ventromedial Hypothalamus and this Action by Leptin is Required for Normal Body Weight Homeostasis." Publishing in Neuron Vol. 49, pages 191-203, January 19, 2006, DOI 10.1016/j.neuron.2005.12.021 www.neuron.org

Cell Press

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