Resistance To Leptin Contributes To Obesity

August 01, 1997

Insensitivity to the protein leptin, which helps the body regulate its fat stores, contributes to obesity in mice according to the first formal study of leptin intolerance, report scientists in the Aug. 5 Proceedings of the National Academy of Sciences. The findings also provide clues about leptin's action in the nervous system and may help to explain some forms of obesity that affect humans, including more than 50 million overweight adult Americans, the researchers note.

"We knew obese mice and humans generally have high levels of leptin in their blood, which suggested that the protein was not fully active. Our new research directly shows that resistance to leptin can cause obesity," explains senior author Jeffrey Friedman, M.D., Ph.D., professor at The Rockefeller University and an investigator with Howard Hughes Medical Institute (HHMI).

Some investigators have suggested that leptin's principal role is to suppress the body's response to starvation. The new study also suggests that receiving extra leptin adjusts a mouse's 'set point' for the body weight to a lower-- but stable level --by reducing food intake without an accompanying decrease in energy use.

"These data confirm that leptin plays an important role in the body's response to weight gain. This result suggests that lean animals increase their production of leptin to return their weight to the set point," explains first author Jeffrey L. Halaas, B.S., biomedical fellow at Rockefeller. "Also, leptin acts to blunt the reduction in energy use that typically follows a reduction in the number of calories eaten."

In previous studies, Friedman and his colleagues discovered leptin and documented weight loss in genetically obese and normal mice given daily injections of the protein for two weeks. These early studies required high dose injections of leptin. In the current study, much lower doses were effective in reducing weight when the hormone was delivered as a constant infusion. While receiving leptin, the mice ate less and had a relative increase in their energy use compared to fasted mice. Leptin, a product of the obese gene, is made in fat and then is released into the blood stream, by which it travels to the brain.

Obesity, defined as being more than 20 percent above a healthy weight, affects one in three Americans and is a major risk factor for diabetes, heart disease, high blood pressure, stroke, sleep apnea, gallstones, some cancers and forms of arthritis, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the federal government's National Institutes of Health. NIDDK supported the research, along with the Robert J. Jr. and Helen C. Kleberg Foundation.

In the new study, Friedman and his coinvestigators from Columbia University, St. Luke's-Roosevelt Hospital Center, University of Melbourne and the Howard Florey Institute of Experimental Physiology and Medicine, found that three strains of obese mice, all with normally high levels of leptin, are overweight because they have varying degrees of insensitivity to the protein. The team examined the effect of leptin given during a 30-day period as infusions either into the fat tissue under the skin or directly into the fluid that bathes the brain and spinal column. This innovative technique, called ICV infusion, was developed by coauthor Dr. Derek A. Denton of the Howard Florey Institute in Melbourne, Australia.

Normal weight, lean mice receiving leptin by either method lost significant weight and fat, with low doses delivered via ICV infusion having the same effects as high doses given as subcutaneous infusions into the fat tissue. For example, during ICV infusion, at a constant rate of 8 nanograms (ng) per hour, lean mice lost 15 percent of their body weight, yet this dose had no effect when given to other lean mice by the subcutaneous injection.

"The difference between the increased potency of leptin in lean mice receiving the protein via ICV infusion and those receiving subcutaneous injections shows that the central nervous system, in particular the hypothalamus, is an important site of leptin action," says Friedman. "Indeed, chronic ICV infusions of very low doses of leptin replicate the weight-reducing effects of much higher doses of leptin given by injection. The basis for this apparent difference is not clear, but may suggest that the transport of leptin across the blood-brain barrier, which allows leptin to enter the brain from the body's blood stream, may be an important step in the body's processing of leptin's signal."

Specifically, in normal, lean mice, injecting leptin subcutaneously at an infusion rate of 200 ng per hour, for example, led to an increase in blood levels, from 5 to 7 ng/milliliter, and resulted in a 5 percent reduction in weight. A doubling of leptin levels led to a 9 percent reduction in weight, while a five-fold increase in leptin levels yielded a 15 percent weight loss.

Other lean mice receiving leptin through ICV infusion rapidly lost fat, reaching their lowest weight by the eighth day of treatment and maintained it for the remainder of the 30-day infusion period. The mice reduced their food intake to its lowest level, a drop of more than 50 percent, by the third day, but their food intake crept back to original levels by the eighth day. After the 30 days of ICV, the researchers replaced the cerebrospinal fluid and the mice quickly recovered their weight by eating more food.

To compare leptin's affects via injection and ICV infusion among overweight mice, the researchers selected strains of mice with different types of obesity. One type, the Diet Induced Obese (DIO) mouse, is lean when fed regular mouse chow, but has an inherited predisposition to develop obesity when fed a diet in which 45 percent of the calories are from fat.

The second strain, the New Zealand Obese (NZO) mouse, is overweight because of the action of several genes. The third kind of mouse, called Yellow Agouti (Ay), is obese due to single copy of a mutant gene.

In the leptin injection study, NZO and Ay mice did not respond to subcutaneous leptin doses of 5 micrograms per hour, a 10 times greater dose than required to achieve a maximum response in the lean mice. The DIO mice lost weight when give injections of leptin, but were less sensitive than the lean mice. Also, the DIO mice fed the regular diet had a greater response to high doses of injected leptin than DIO on high-fat diets: losses of 83 vs. 30.5 percent of body fat. In the ICV infusion studies, NZO mice responded to low doses of 5 ng per hour, but doses 100 times greater yielded modest weight loss in the Ay mice.

"Because the Ay mice required substantially higher doses than that needed in lean and NZO mice for weight loss, leptin resistance in the Ay mice may result from a defect in the nerve pathway activated by leptin," Friedman says. "In NZO mice, a decrease in the transport of leptin into the cerebrospinal fluid may cause the obesity."

Friedman, Halaas and Denton's coauthors include: Naseem Fidahusein, B.S., at Rockefeller; Carol Boozer, D.Sc., at Columbia University School of Medicine and the Obesity Research Center at St. Luke's-Roosevelt Hospital Center; and John Blair-West, Ph.D., of the University of Melbourne.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created five centers to foster collaborations among scientists to pursue investigations of Alzheimer's Disease, of biochemistry and structural biology, of human genetics, of sensory neurosciences and of the links between physics and biology.
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