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Editorial   |    
Brain, Bone, and Body Mass: Fat is Beautiful Again
Thomas A. Einhorn, MD
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Deputy Editor for Current Concepts Reviews

J Bone Joint Surg Am, 2001 Dec 01;83(12):1782-1782
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Throughout history, a voluptuous or husky body habitus has been associated with affluence, beauty, and, in many societies, health. It was not until the middle of the twentieth century that Western civilizations began to express a cosmetic preference for a slender body build; this was followed by actuarial data showing that life expectancy is reduced when body-mass index (body mass in kilograms divided by the square of the height in meters) is 20% above the ideal1. However, independent of one’s health, or of the "beholder’s eye" in which the "beauty lies," the belief that obesity is largely a result of a lack of willpower has recently been challenged. Studies of twins, analyses of familial aggregation, adoption studies, and animal models of obesity all lead to the conclusion that obesity is the result of both genetic and environmental factors2-4. Over a half-century ago it was shown that signals reflecting nutritional status are sensed by the hypothalamus5. In the past five years, a complex physiological system has been elucidated identifying leptin, a small polypeptide hormone secreted primarily by adipocytes and acting mainly on the hypothalamus, as being essential to the control of body weight and, directly or indirectly, gonadal function. Accordingly, mice deficient in leptin or its receptor are obese and hypogonadic6,7. It is no surprise that leptin has received much attention in the lay media for its potential role in controlling body weight.
So what does this have to do with orthopaedic surgery? In this issue of The Journal, the Current Concepts Review by Haberland et al. presents a "new paradigm in skeletal biology," in which the regulation of bone mass occurs through a hypothalamic control mechanism in the central nervous system and these pathways involve leptin signaling and are associated with body weight7. This article describes how leptin-deficient and leptin receptor-deficient mice are obese and hypogonadic and show an increase in bone formation leading to high bone mass. Moreover, while there is no leptin signaling in osteoblasts, intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type (normal) mice. Hence, a picture emerges in which bone and body mass are physiologically linked through the central nervous system, leading to the concept of a central control of bone mass and its disorders8. Besides the many questions raised by these studies, the notion that pharmacological manipulation of the leptin pathway may be a novel therapeutic approach to prevent and/or treat osteoporosis seems obvious.
These observations have ramifications in orthopaedic surgery that could extend beyond their applications to our understanding or treatment of osteoporosis and related disorders. For example, just last week I performed a total hip arthroplasty in an obese, sixty-year-old patient whose femoral cortices appeared exceptionally thick on radiographs. My decision to implant a stem without cement was influenced by my new understanding of the central regulation of bone mass and the belief that bone formation (and possibly ingrowth) may be enhanced. As has recently been shown, leptin expression and leptin levels in obese individuals are elevated compared with those in lean individuals9 but, in obesity, there is resistance to the biological effects of leptin10,11. This state of leptin resistance provides a molecular hypothesis to explain the protective effect of obesity on bone mass in humans. Although earlier reports have invoked the effects of body weight on bone mineral density through weight-bearing-mediated mechanical pathways12, and while these effects may indeed play an essential role in the accrual of bone mass, the body of evidence from recent studies reviewed by Haberland et al. presents a convincing argument for the central control of bone mass. This is particularly true with regard to the prevention of bone loss in states in which one would expect to see it, such as hypogonadism or hypercortisolism.
Does this mean that we should now tell our patients to gain weight? I do not think so. Instead, it is the recognition of the control of fat and bone metabolism by the central nervous system that provides a new understanding of the biology of the skeletal system. While some of the molecular biology discussed in this month’s Current Concepts Review may seem esoteric, I encourage you to read this article and to think about its ramifications. Every so often, a new discovery emerges that really requires our attention. I think this is one of them.
Harris T, Cook EF, Garrison R, Higgins M, Kannel W,Goldman L. Body mass index and mortality among nonsmoking older persons. The Framingham Heart Study. JAMA,1988;259: 1520-4. 2591520  1988  [PubMed][CrossRef]
 
Friedman JM,Halaas JL. Leptin and the regulation of body weight in mammals. Nature,1998;395: 763-70. 395763  1998  [PubMed][CrossRef]
 
Stunkard AJ, Harris JR, Pedersen NL,McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med,1990;322: 1483-7. 3221483  1990  [PubMed][CrossRef]
 
Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia,1978;14: 141-8. 14141  1978  [PubMed][CrossRef]
 
Hetherington AW,Ranson SW. The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol,1942;136: 609-17. 136609  1942 
 
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature,1994;372: 425-32. 372425  1994  [PubMed][CrossRef]
 
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J,et al. Identification and expression cloning of a leptin receptor, OB-R. Cell,1995;83: 1263-76. 831263  1995  [PubMed][CrossRef]
 
Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM,Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell,2000;100: 197-207. 100197  2000  [PubMed][CrossRef]
 
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S,et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med,1995;1: 1155-61. 11155  1995  [PubMed][CrossRef]
 
Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK,Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet,1996;348: 159-61. 348159  1996  [PubMed][CrossRef]
 
Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE,Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell,1998;4: 619-25. 4619  1998  [CrossRef]
 
Felson DT, Zhang Y, Hannan MT,Anderson JJ. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res,1993;8: 567-73. 8567  1993  [PubMed][CrossRef]
 

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References

Harris T, Cook EF, Garrison R, Higgins M, Kannel W,Goldman L. Body mass index and mortality among nonsmoking older persons. The Framingham Heart Study. JAMA,1988;259: 1520-4. 2591520  1988  [PubMed][CrossRef]
 
Friedman JM,Halaas JL. Leptin and the regulation of body weight in mammals. Nature,1998;395: 763-70. 395763  1998  [PubMed][CrossRef]
 
Stunkard AJ, Harris JR, Pedersen NL,McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med,1990;322: 1483-7. 3221483  1990  [PubMed][CrossRef]
 
Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia,1978;14: 141-8. 14141  1978  [PubMed][CrossRef]
 
Hetherington AW,Ranson SW. The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol,1942;136: 609-17. 136609  1942 
 
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature,1994;372: 425-32. 372425  1994  [PubMed][CrossRef]
 
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J,et al. Identification and expression cloning of a leptin receptor, OB-R. Cell,1995;83: 1263-76. 831263  1995  [PubMed][CrossRef]
 
Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM,Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell,2000;100: 197-207. 100197  2000  [PubMed][CrossRef]
 
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S,et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med,1995;1: 1155-61. 11155  1995  [PubMed][CrossRef]
 
Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK,Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet,1996;348: 159-61. 348159  1996  [PubMed][CrossRef]
 
Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE,Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell,1998;4: 619-25. 4619  1998  [CrossRef]
 
Felson DT, Zhang Y, Hannan MT,Anderson JJ. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res,1993;8: 567-73. 8567  1993  [PubMed][CrossRef]
 
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These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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