Head First: Defective brain response to insulin could trigger diabetes and obesity (Diabetes; Insulin resistance)
Authors: Leslie Mitch 
Published: August 2003

If willpower doesn't stop you from reaching for that second piece of cake, the problem might still be in your head. New research on corpulent rats shows that the hormone insulin helps the brain determine how much food is enough. The findings solidify the idea that insulin doesn't govern weight solely through its effect on body tissues and might inspire new ways to prevent diabetes and obesity.
Scientists once thought of insulin as a provincial hormone that works mainly outside the brain, controlling blood sugar by prodding muscle and liver cells to take up and store glucose. But recent work hinted that insulin also goads neurons in the brain, helping them regulate eating and energy use. Two years ago, Harvard researchers produced mice that lacked insulin receptors throughout the nervous system. The mice overate and grew chunky, which suggests that insulin normally helps restrain hunger or accelerate metabolism. But the rodents also developed reproductive flaws. Because signals from the reproductive system can affect fat storage, the mice's girth could have resulted from these defects rather than from a scarcity of insulin receptors.
To pin down the hormone's role, Obici and colleagues pruned insulin receptors from only one region of the hypothalamus, the brain structure that governs appetite and metabolism, among other processes. The researchers created short strands of DNA that mirror a segment of the receptor gene. The team implanted catheters that delivered these so-called antisense strands directly to the part of the rat hypothalamus involved in maintaining energy balance. Once there, the molecules stuck to the receptor gene's RNA message and blocked production of the protein.
The manipulation slashed the number of insulin receptors in the brain region by 80%. The treated rats binged, snarfing about 50% more food than the control group, which had received a dummy antisense strand, ate. The ravenous rodents also packed on more than twice as much fat, and their livers were less responsive to insulin, a condition known as insulin resistance. That the rodents displayed hallmarks of obesity and diabetes--overeating, weight gain, and insulin resistance--suggests that reductions in the number of insulin receptors in the hypothalamus might spur these diseases, says Luciano Rossetti, a diabetes researcher at Albert Einstein College of Medicine in New York City and head of the team. If so, treatments that correct the deficiency might fend off obesity and diabetes.
"The study is an important addition to our understanding of the role of insulin signaling in the brain," says Jeffrey Flier, an endocrinologist at Harvard University. However, he cautions that no one has demonstrated that the brains of overweight or diabetic people bear fewer insulin receptors than normal. Obesity researcher Stephen Woods of the University of Cincinnati also praises the work, saying that it might help explain why another weight-control hormone, leptin, failed "as the magic bullet that would cure obesity." The evidence suggests a dual-control system, he says, in which insulin cooperates with leptin to tell us when to step away from the dinner table.
--Mitch Leslie

S. Obici, Z. Feng, G. Karkanias, D. G. Baskin, L. Rossetti, Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats.
Nat. Neuro.
5
, 566-572 (2002).
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