Scientists Detail Hormone’s Role in the Impulse to Eat

Scientists today are a step closer to understanding why it is so hard to lose weight.

Scientists today are a step closer to understanding why it is so hard to lose weight. In papers published in the journal Science, two research teams describe newfound powers of leptin, the mysterious hormone that helps govern hunger and satiety. It appears that the substance, produced by fat cells, plays a crucial role in establishing the brain’s circuitry before birth, and retains the ability to subtly rewire those neural connections throughout life. Those observations, made in mice but which scientists believe may also apply to humans, offer a peek at the cellular workings of one of life’s few essential impulses: the drive to eat. The papers also shed light on why many people seem to have a physical “set point” — a weight their body seeks to maintain despite their efforts to change it. “The wiring diagram of the system that regulates feeding may be different in the obese than in the lean, and that may explain why lifestyle changes aren’t generally effective for achieving substantial weight loss over the long term,” said Jeffrey M. Friedman, the scientist who helped lead one of the teams. Friedman, of the Howard Hughes Medical Institute at Rockefeller University in New York, discovered leptin 10 years ago. When it is released by fat cells into the bloodstream, leptin works to suppress appetite. A deficiency of the hormone leads to overeating and obesity. However, hopes for easily losing weight by simply taking leptin have not been borne out by human experiments. The new research helps explain why — namely, that leptin works in a delicately calibrated system whose workings may be established at least in part even before birth. The experiments were done in mice that are genetically incapable of making leptin. These so-called ob/ob animals are grossly overweight compared with their brethren. In both studies, researchers examined cells in an ancient part of the brain called the hypothalamus. Although it constitutes less than 1 percent of the brain’s volume, the hypothalamus contains neural circuits governing numerous vital functions, including body temperature, heart rate, blood pressure, the water content of blood and food intake. One region contains two cell types with opposite actions on eating. When NPY cells are stimulated, feeding increases and fat accumulates; when POMC cells are stimulated, feeding decreases and, eventually, so does body mass. Both types are constantly active, and the relative intensity of their action is one of several things that determine how often and how much an animal eats. Friedman, along with Shirly Pinto of Rockefeller University and Tamas L. Horvath of Yale University, measured both the electrical activity and the number of intracellular connections, called synapses, in both types of cells. When a mouse is leptin-deficient, the NPY cells that stimulate feeding are more active, and POMC cells are less active, compared with normal animals. In the normal animals’ NPY cells, there were more inhibitory than stimulatory connections coming to them from other cells. In the ob/ob mice, that situation was reversed. The effect of this was to make the leptin-deficient animals eat more and make more fat cells in a futile effort to make leptin. The researchers then gave the hormone to the deficient animals and watched what happened. Once exposed to enough leptin, there was a sixfold reduction in the number connections to the NPY cells that stimulate them and promote feeding, and a near doubling of the satiety-inducing connections. Reciprocal changes were seen in the POMC cells. This subtle rewiring occurred within six hours of giving the animals leptin. Two days later, their feeding slowed, and 12 days later their weight began to fall. While further research must be done to learn what happens in the brain during weight loss, the mouse experiments might determine the “set point” this way: When a person loses fat, leptin levels in the blood fall. Hypothalamic wiring might then change so that NPY cells get more input that stimulates feeding, and POMC cells get more connections that blunt satiety. “The net effect is that you would have a stimulus to eat more, eventually deposit more fat and make more leptin — at which point your wiring diagram normalizes,” Friedman said. In the second experiment, Richard B. Simerly and Sebastien G. Bouret of the Oregon National Primate Research Center looked at the connections that NPY and POMC cells make to other regions of the hypothalamus. What they found, in short, was that in ob/ob mice, the leptin-sensitive cells make many fewer connections. The deficient animals do not experience a surge of leptin that occurs predictably soon after birth. Curiously, however, that surge does not affect eating behavior. What it appears to do, instead, is tell the cells to grow and make specific links. When the Oregon team gave the hormone to ob/ob mice in a specific “sensitive” period after birth, the brains of the mice grew nearly normal connections, but when the hormone was given in adulthood, they did not. This suggests that while leptin may modify an adult animal’s leptin circuitry, it cannot redesign it. Simerly speculated that there may be variations in people’s sensitivity to leptin based on how their hypothalamic circuits formed in fetal life, or just after birth. That, in turn, might affect a person’s propensity to be fat in adulthood. (Source: Wasington Post, April 2004)