Perspectives in Biology and Medicine

ETIOLOGIC FACTORS IN OBESITY AND LEANNESS JAY TEPPERMAN, M.D.* In the early years ofthe last decade, a beginning student ofthe problem of obesity and leanness was struck by the confident assertion that all obesity was simply due to overeating. Most obesity was, in fact, called "simple obesity." Fat people were all gluttons—pitiful, perhaps, and occasionally tortured by unbearable life-situations into stuffing themselves with lethal calories—but gluttons nonetheless. People with strength of character were able to respond to the challenges of life gracefully and remain attractively lean in the face of adversity. If a physiologist (possibly one with a tendency to obesity) ventured to suggest that there might be metabolic differences among people that predisposed some to leanness and others to obesity, he was looked upon with suspicion or, possibly, accused of attempting to repeal the laws of thermodynamics. Had not Newburgh (i) demonstrated that, when an obese patient is underfed, his weight loss follows a predictable line? Surely this experiment indicated that the metabolic machinery ofobese people was the same as that ofnormal people and that if the fat people of the world just exercised a little self-control they could avoid obesity and all its horrible sequelae. The idea of a metabolic or constitutional predisposition to obesity was regarded as a refuge of obese people, who were eager to transfer accountability for their obesity from themselves to their near and remote ancestors or to Fate. In 1958 a beginning student would find a rather different attitude toward this problem. In the first place, he would discover bewilderment in place ofcertainty. This represents a kind ofprogress, for it is often a candid * The author is Professor ofExperimental Medicine, Department ofPharmacology, State University ofNew York, Upstate Medical Center, Syracuse, New York. 293 admission of confusion that precedes the development of insight and understanding. Now we are by no means sure that there are not metabolic differences among people which predispose some to obesity and some to leanness. Many studies on experimental animals (see Mayer's review, 2) strongly suggest that a tendency to obesity can be inherited, although a single, determining biochemical trait which will "explain" the obesityproneness has not yet been described for any known form of genetically linked obesity. When one re-examines Camerer's and Schleicher's photographs oflean and obese identical twins after seventeen years (reproduced in Rony's monograph, 3), they acquire a new significance. It is interesting to reflect upon some of the causes for the change that has occurred since 1940. Some, like the studies on hereditary obesity mentioned above, are quite obvious, but others are not. Foremost among the less obvious, I would place the exciting development ofmodern biochemical genetics, begun in a mold—Neurospora—and extended to bacteria. One's imagination reels in contemplating the implications of this work for human biology, particularly when one thinks at the same time ofthe fact that the genetic material itself has been clearly identified in some species. At present it is permissible to imagine that each person begins as a couple of embracing coils of DNA which are elaborately encoded to yield an organism whose cells contain metabolic machinery of a certain potential. From what we can observe about biologic variation, we can postulate that, if it were possible to assay the enzyme activity for every reaction ofevery cell, a group ofindividuals would showa normal distribution curve for each activity. Even with allowance for the fact that many ofthe reactions dependent on enzymes are not rate-limiting, there would still be an enormous number of distribution curves that would characterize the group. Ifit were possible mathematically to integrate the individual enzyme activities ofeach individual into an expression that would characterize the individual and if one were to perform this operation for all the individuals in a large group, one would be left with a normal distribution curve ofthe composite curves. In the light ofwhat we know about the complexity ofthe nature ofthe intermediary metabolic processes and about the obvious variability ofindividuals with respect to many visually apparent traits we know to be genetically linked, it would be nothing less than astonishing ifevery person in the world derived precisely the same amount...