Correspondence
Leptin-Replacement Therapy in Lipodystrophy
N Engl J Med 2002; 346:2008-2010June 20, 2002
- Article
To the Editor:
Oral et al. (Feb. 21 issue)1 demonstrate convincingly that treatment with leptin decreases triglyceride levels, improves insulin resistance, and ameliorates diabetes in patients with lipodystrophy and leptin deficiency. Minokoshi et al. have recently demonstrated that leptin can activate the enzyme AMP-activated protein kinase in skeletal muscle, thereby increasing lipid combustion and glucose uptake and establishing a molecular basis for the lipid-lowering and insulin-sensitizing effect of leptin described in this study.2
In the light of their results, Oral et al. suggest that leptin is the chief fat-derived hormone required for glucose homeostasis. Used at physiologic levels, however, leptin did not totally reverse the diabetic phenotype. Similarly, in transgenic mouse models of severe lipoatrophy, insulin resistance and diabetes are not entirely reversed by physiologic levels of leptin.3 In these models, complete reversal of the diabetic phenotype is obtained with pharmacologic levels of leptin4 or by fat transplantation,5 suggesting that in the absence of fat, leptin is not sufficient to maintain glucose and lipid homeostasis. Like leptin, adiponectin is an adipocytokine that stimulates muscle lipid oxidation and prevents liver steatosis, thereby improving sensitivity to insulin. Indeed, insulin resistance in lipoatrophic mice is completely reversed by the combination of physiologic doses of leptin and of adiponectin but is only partially reversed by either cytokine alone.6 Since patients with lipodystrophy and transgenic mouse models of the disorder have similar responses to treatment with leptin, it is possible that they would have similar responses to the administration of adiponectin. Determination of the adiponectin level in this subgroup of patients might be of interest for future clinical trials involving both leptin and adiponectin in patients with lipodystrophy.
6 ReferencesFranck Mauvais-Jarvis, M.D.
Saint-Louis Hospital, 75010 Paris, France
fmauvaisjarvis@aol.com 1
Oral EA ,Simha V ,Ruiz E , et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-578
Full Text | Web of Science | Medline2
Minokoshi Y ,Kim YB ,Peroni OD , et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339-343
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Gavrilova O ,Marcus-Samuels B ,Leon LR ,Vinson C ,Reitman ML . Leptin and diabetes in lipoatrophic mice. Nature 2000;403:850-851
Web of Science | Medline4
Ebihara K ,Ogawa Y ,Masuzaki H , et al. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 2001;50:1440-1448
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Gavrilova O ,Marcus-Samuels B ,Graham D , et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000;105:271-278
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Yamauchi T ,Kamon J ,Waki H , et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941-946
CrossRef | Web of Science | Medline
To the Editor:
We found that when food intake was restricted in patients with lipodystrophy, elevated glucose and triglyceride levels returned to virtually normal values within days.1 In persons who lack a storage organ for surplus calories, the result, although welcomed, was not entirely unexpected. The caloric intake of the patients in the study by Oral et al. decreased and they lost weight while receiving leptin. The possible influence of food restriction was studied in only one of their patients. However, the reduction in the values for triglycerides, insulin, and glucose when leptin was given coincided with the appearance of pancreatitis and, presumably, a decrease or cessation of oral intake. Until there is more substantial evidence of the favorable effect of leptin in patients with lipodystrophy, we suggest that restricted caloric intake remains a simpler yet effective therapeutic tool.
1 ReferencesJoseph Wolfsdorf, M.B., B.Ch.
Children's Hospital, Boston, MA 02115Ab Sadeghi-Nejad, M.D.
Boris Senior, M.D.
Tufts University School of Medicine, Boston, MA 02111
bodosen@attbi.com 1
Wolfsdorf JI ,Sadeghi-Nejad A ,Senior B . Lipodystrophy: a simple and effective approach to therapy. Pediatr Res 1979;13:484-484 abstract.
Web of Science
To the Editor:
The optimal dose of recombinant leptin in patients with lipodystrophy and possibly in those with other insulin-resistant states remains to be carefully determined. In the study by Oral et al., the patients receiving leptin had a marked decrease in mean (±SE) food intake (from 2680±250 kcal per day at base line to 1600±150 kcal per day after four months), which was associated with a significantly decreased resting metabolic rate, in contrast to an expected increase. The mean weight loss was 3.6±0.9 kg. Because both animals and humans with congenital leptin deficiency are supersensitive to leptin treatment,1-3 such a negative energy balance might be a limiting factor for long-term use of leptin in patients with lipodystrophy.
One patient had an exacerbation of hypertension during the course of treatment, despite the marked decrease in food (and thus probably salt) intake. Leptin is known to have sympathoexcitatory actions leading to hypertension.4 Because leptin may also be involved in the control of reproduction, thyroid and adrenal axes, and gastrointestinal and immune functions, even physiologic doses of leptin should be carefully monitored in leptin-deficient patients.
4 ReferencesAkio Inui, M.D., Ph.D.
Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
inui@med.kobe-u. ac. jp 1
Farooqi IS ,Jebb SA ,Langmack G , et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879-884
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Friedman JM ,Halaas JL . Leptin and the regulation of body weight in mammals. Nature 1998;395:763-770
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Inui A . Feeding and body-weight regulation by hypothalamic neuropeptides -- mediation of the actions of leptin. Trends Neurosci 1999;22:62-67
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Correia ML ,Haynes WG ,Rahmouni K ,Morgan DA ,Sivitz WI ,Mark AL . The concept of selective leptin resistance: evidence from agouti yellow obese mice. Diabetes 2002;51:439-442
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Author/Editor Response
The authors reply:
To the Editor: As Dr. Mauvais-Jarvis states, activation of the enzyme AMP-activated kinase by leptin may be a key mechanism in the explanation of the effects observed in our patients. This hypothesis requires further testing. The effect of leptin in any species may be modified by the genetic background. We stated in our discussion that leptin is the main adipocyte hormone that maintains insulin sensitivity; however, we acknowledge that it is not the only one.1 The effect of other adipocyte hormones in humans is an open and important question.
We agree with Dr. Wolfsdorf and colleagues that dietary control is the central tenet of treatment in all diabetic and metabolic syndromes. However, in our patients, the best metabolic control we could achieve with diet and antidiabetic therapy was indicated by the base-line data we presented. Hyperphagia is a strong drive that is hard to overcome by medical advice and rational discussion with these patients, like the hyperphagia observed in patients with a congenital absence of leptin2 or leptin receptor.3 The administration of leptin clearly had an effect in ameliorating the extreme hyperphagia as well as improving the metabolic values in our patients. The pancreatitis-like syndrome occurred when leptin was withdrawn in one patient, while food intake was kept constant, and the occurrence of the syndrome coincided with the apparent increase in triglyceride levels. The withdrawal of leptin resulted in a clear rise in fasting insulin and triglyceride levels despite the constant caloric intake until the development of pancreatitis-like symptoms. Although our data are not sufficient to prove the direct effects of leptin on total-body insulin sensitivity and lipid metabolism alone, taken together with the results of pair-feeding experiments in animal models,4 they support the hypothesis that leptin is an insulin sensitizer in addition to its effect on food intake.
Finally, we would like to make the following points about the safety of leptin therapy, in response to Dr. Inui's comments. All the patients we described have continued to receive leptin therapy for up to a year without further weight loss and with stable energy expenditure at rest. We did not expect the resting energy expenditure to increase with leptin therapy, since this observation is limited to rodents, as we stated in our discussion. We have not noted any adverse effects on the hypothalamic–pituitary–adrenal5 or thyroid axis and have noted only favorable effects on the reproductive system,5 as well as the immune system. The exacerbation of hypertension in one patient that we noted in our report was an isolated event that occurred on the first day of treatment and did not recur in the patient, despite continued therapy.
5 ReferencesElif Arioglu Oral, M.D.
Elaine Ruiz, C.R.N.P.
Phillip Gorden, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892
eliforal@umich.edu 1
Oral EA ,Simha V ,Ruiz E , et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-578
Full Text | Web of Science | Medline2
Montague CT ,Farooqi IS ,Whitehead JP , et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-908
CrossRef | Web of Science | Medline3
Clement K ,Vaisse C ,Lahlou N , et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398-401
CrossRef | Web of Science | Medline4
Shimomura I ,Hammer RE ,Ikemoto S ,Brown MS ,Goldstein JL . Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999;401:73-76
CrossRef | Web of Science | Medline5
Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab (in press).
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