Insensitivity to the protein leptin, which helpsthe body regulate its fat stores, contributes to obesityin mice according to the first formal study of leptinintolerance, report scientists in the Aug. 5 Proceedingsof the National Academy of Sciences. The findings alsoprovide clues about leptin's action in the nervoussystem and may help to explain some forms of obesitythat affect humans, including more than 50 millionoverweight adult Americans, the researchers note.
"We knew obese mice and humans generally have highlevels of leptin in their blood, which suggested thatthe protein was not fully active. Our new researchdirectly shows that resistance to leptin can causeobesity," explains senior author Jeffrey Friedman, M.D.,Ph.D., professor at The Rockefeller University and aninvestigator with Howard Hughes Medical Institute(HHMI).
Some investigators have suggested that leptin'sprincipal role is to suppress the body's response tostarvation. The new study also suggests that receivingextra leptin adjusts a mouse's 'set point' for the bodyweight to a lower-- but stable level --by reducing foodintake without an accompanying decrease in energy use.
"These data confirm that leptin plays an importantrole in the body's response to weight gain. This resultsuggests that lean animals increase their production ofleptin to return their weight to the set point,"explains first author Jeffrey L. Halaas, B.S.,biomedical fellow at Rockefeller. "Also, leptin acts toblunt the reduction in energy use that typically followsa reduction in the number of calories eaten."
In previous studies, Friedman and his colleaguesdiscovered leptin and documented weight loss ingenetically obese and normal mice given daily injectionsof the protein for two weeks. These early studiesrequired high dose injections of leptin. In the currentstudy, much lower doses were effective in reducingweight when the hormone was delivered as a constantinfusion. While receiving leptin, the mice ate less andhad a relative increase in their energy use compared tofasted mice. Leptin, a product of the obese gene, ismade in fat and then is released into the blood stream,by which it travels to the brain.
Obesity, defined as being more than 20 percentabove a healthy weight, affects one in three Americansand is a major risk factor for diabetes, heart disease,high blood pressure, stroke, sleep apnea, gallstones,some cancers and forms of arthritis, according to theNational Institute of Diabetes and Digestive and KidneyDiseases (NIDDK), part of the federal government¹sNational Institutes of Health. NIDDK supported theresearch, along with the Robert J. Jr. and Helen C.Kleberg Foundation.
In the new study, Friedman and his coinvestigatorsfrom Columbia University, St. Luke's-Roosevelt HospitalCenter, University of Melbourne and the Howard FloreyInstitute of Experimental Physiology and Medicine, foundthat three strains of obese mice, all with normally highlevels of leptin, are overweight because they havevarying degrees of insensitivity to the protein. Theteam examined the effect of leptin given during a 30-dayperiod as infusions either into the fat tissue under theskin or directly into the fluid that bathes the brainand spinal column. This innovative technique, calledICV infusion, was developed by coauthor Dr. Derek A.Denton of the Howard Florey Institute in Melbourne,Australia.
Normal weight, lean mice receiving leptin by eithermethod lost significant weight and fat, with low dosesdelivered via ICV infusion having the same effects ashigh doses given as subcutaneous infusions into the fattissue. For example, during ICV infusion, at a constantrate of 8 nanograms (ng) per hour, lean mice lost 15percent of their body weight, yet this dose had noeffect when given to other lean mice by the subcutaneousinjection.
"The difference between the increased potency ofleptin in lean mice receiving the protein via ICVinfusion and those receiving subcutaneous injectionsshows that the central nervous system, in particular thehypothalamus, is an important site of leptin action,"says Friedman. "Indeed, chronic ICV infusions of verylow doses of leptin replicate the weight-reducingeffects of much higher doses of leptin given byinjection. The basis for this apparent difference isnot clear, but may suggest that the transport of leptinacross the blood-brain barrier, which allows leptin toenter the brain from the body's blood stream, may be animportant step in the body's processing of leptin'ssignal."
Specifically, in normal, lean mice, injectingleptin subcutaneously at an infusion rate of 200 ng perhour, for example, led to an increase in blood levels,from 5 to 7 ng/milliliter, and resulted in a 5 percentreduction in weight. A doubling of leptin levels led toa 9 percent reduction in weight, while a five-foldincrease in leptin levels yielded a 15 percent weightloss.
Other lean mice receiving leptin through ICVinfusion rapidly lost fat, reaching their lowest weightby the eighth day of treatment and maintained it for theremainder of the 30-day infusion period. The micereduced their food intake to its lowest level, a drop ofmore than 50 percent, by the third day, but their foodintake crept back to original levels by the eighth day.After the 30 days of ICV, the researchers replaced thecerebrospinal fluid and the mice quickly recovered theirweight by eating more food.
To compare leptin's affects via injection and ICVinfusion among overweight mice, the researchers selectedstrains of mice with different types of obesity. Onetype, the Diet Induced Obese (DIO) mouse, is lean whenfed regular mouse chow, but has an inheritedpredisposition to develop obesity when fed a diet inwhich 45 percent of the calories are from fat. Thesecond strain, the New Zealand Obese (NZO) mouse, isoverweight because of the action of several genes. Thethird kind of mouse, called Yellow Agouti (Ay), is obesedue to single copy of a mutant gene.
In the leptin injection study, NZO and Ay mice didnot respond to subcutaneous leptin doses of 5 microgramsper hour, a 10 times greater dose than required toachieve a maximum response in the lean mice. The DIOmice lost weight when give injections of leptin, butwere less sensitive than the lean mice. Also, the DIOmice fed the regular diet had a greater response to highdoses of injected leptin than DIO on high-fat diets:losses of 83 vs. 30.5 percent of body fat. In the ICVinfusion studies, NZO mice responded to low doses of 5ng per hour, but doses 100 times greater yielded modestweight loss in the Ay mice.
"Because the Ay mice required substantially higherdoses than that needed in lean and NZO mice for weightloss, leptin resistance in the Ay mice may result from adefect in the nerve pathway activated by leptin,"Friedman says. "In NZO mice, a decrease in thetransport of leptin into the cerebrospinal fluid maycause 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 theObesity Research Center at St. Luke's-Roosevelt HospitalCenter; and John Blair-West, Ph.D., of the University ofMelbourne.
Rockefeller began in 1901 as the RockefellerInstitute for Medical Research, the first U.S.biomedical research center. Rockefeller faculty membershave made significant achievements, including thediscovery that DNA is the carrier of genetic informationand the launching of the scientific field of modern cellbiology. The university has ties to 19 Nobel laureates,including the president, Torsten N. Wiesel, M.D., whoreceived the prize in 1981. Recently, the universitycreated five centers to foster collaborations amongscientists to pursue investigations of Alzheimer'sDisease, of biochemistry and structural biology, ofhuman genetics, of sensory neurosciences and of thelinks between physics and biology.
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