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Effect of Leptin Replacement on Intrahepatic and Intramyocellular Lipid Content in Patients With Generalized Lipodystrophy

¹ Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
² Division of Hypertension, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
³ Center for Human Nutrition, Unviersity of Texas Southwestern Medical Center, Dallas, Texas
⁴ Amgen, Inc., Thousand Oaks, California

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS ADDENDUM References

 
OBJECTIVE—To investigate whether leptin-induced improvements in glycemic control, hyperlipidemia, and insulin sensitivity in hypoleptinemic patients with generalized lipodystrophies are accompanied by reduction in intrahepatic and intramyocellular lipid (IMCL) accumulation.

RESEARCH DESIGN AND METHODS—We examined the effects 8–10 months of subcutaneous leptin replacement therapy on insulin sensitivity, IMCL, and intrahepatic lipid content in two patients with acquired generalized lipodystrophy and one patient with congenital generalized lipodystrophy. All patients had extreme lack of body fat, low plasma leptin levels, and elevated serum triglycerides, but only two had diabetes. Insulin sensitivity was measured by a high-dose (0.2 IU/kg) insulin tolerance test, as well as by hyperinsulinemic-euglycemic glucose clamp studies in two patients. IMCL and intrahepatic lipid content were measured by ¹H magnetic resonance spectroscopy. All measurements were obtained before and during 2–10 months of leptin therapy.

RESULTS—Glycemic control and lipoprotein levels markedly improved with leptin therapy in the two diabetic patients, and a slight improvement in lipoprotein levels was seen in the nondiabetic patients. Insulin stimulated glucose uptake during 60–120 min of the euglycemic clamp studies, and the rate of glucose disappearance during the insulin tolerance test nearly doubled with leptin therapy. As compared with the baseline period, after 8–10 months of leptin therapy, the mean intrahepatic lipid content was reduced by 80% and the IMCL content was reduced by 42%.

CONCLUSIONS—Reduction in IMCL and intrahepatic lipid content may partly explain leptin-induced improvement in insulin sensitivity in patients with generalized lipodystrophy.

Abbreviations: AGL, acquired generalized lipodystrophy • CGL, congenital generalized lipodystrophy • IMCL, intramyocellular lipid • SC, subcutaneous

	INTRODUCTION

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Patients with generalized lipodystrophies are characterized by a near-complete absence of adipose tissue and severe insulin resistance and its complications, such as impaired glucose tolerance, early-onset diabetes, acanthosis nigricans, hypertriglyceridemia, low HDL cholesterol concentrations, and fatty liver (1). These patients can have either congenital generalized lipodystrophy (CGL) (also known as Berardinelli-Seip syndrome), an autosomal recessive disorder, or acquired generalized lipodystrophy (AGL), likely an autoimmune disorder. Patients with CGL or AGL have low circulating levels of the adipocyte-derived hormone leptin (2,3). Similar metabolic abnormalities and hypoleptinemia have also been observed in genetically altered mice with lipodystrophies (4,5). In the mouse models, metabolic abnormalities mitigated with adequate amounts of fat transplantation (6) or with leptin administration (5). Recently, in a two-center collaborative study (3), subcutaneous (SC) administration of recombinant human leptin for 4 months was reported to significantly improve glycemic control, insulin resistance, and hypertriglyceridemia in nine patients with lipodystrophies (eight of whom had generalized lipodystrophy). Leptin therapy caused an average 3.6-kg weight loss, and self-reported daily energy intake, measured in seven patients, decreased by an average of 1,080 kcal/day. Interestingly, the insulin tolerance test showed near doubling of the K value (rate of glucose disappearance), indicating an improvement in whole-body insulin sensitivity. However, as in the mouse models of lipodystrophy (5,7), energy restriction alone could not fully account for metabolic changes observed with leptin (3).

Recently, there has been accumulating evidence, in both normal lean and obese individuals and in patients with type 2 diabetes, that insulin resistance is strongly associated with increased intramyocellular lipid (IMCL) content (8–12) and with hepatic steatosis (13–15). Interestingly, we previously reported a twofold increase in IMCL content in four patients with CGL (16). Hepatic steatosis has also been reported during early childhood in patients with CGL and AGL (17,18). Therefore, in the present study, we investigated three patients, of whom two were previously reported in the above-mentioned study (3), to determine whether leptin-induced improvement in metabolic parameters and insulin sensitivity in patients with generalized lipodystrophy could be partly explained by reductions in IMCL and intrahepatic lipid content.

	RESEARCH DESIGN AND METHODS

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Patients
Three patients, one with CGL and two with AGL, participated in the leptin trial at the University of Texas Southwestern Medical Center. Informed written consent was obtained, and the study protocol was approved by the Institutional Review Board. The clinical characteristics of the patients studied are briefly summarized below.

Patient 1 was a 31-year-old African- American woman with CGL who has been reported previously (19,20). Recently, compound heterozygous mutations in AGPAT2 gene were reported in this patient (21). One of her sisters also has CGL. She had extreme lack of body fat and a muscular appearance at birth. Diabetes was diagnosed at age 15 years, and extreme hypertriglyceridemia with tubero-erruptive xanthomas was also noted at the same time. She was being treated with 700 units of insulin a day and fenofibrate, in addition to levothyroxine replacement for postsurgical hypothyroidism. She was also on captopril and hydrochlorthiazide for hypertension. Physical examination revealed a height of 1.67 m and weight of 67.5 kg and was remarkable for a generalized loss of fat from the face, trunk, and extremities; coarse, acromegaloid features; marked acanthosis nigricans over the neck, axillae, and abdominal wall; umbilical hernia; and hepatosplenomegaly. At the time of enrollment in the trial, pooled serum leptin level was low at 0.73 ng/ml.

Patient 2 was a 33-year-old non-Hispanic white woman with AGL. She had juvenile dermatomyositis at age 8 years and received treatment with systemic glucocorticoids, azathioprine, and cyclophosphomide, in addition to plasmapheresis. She has been asymptomatic for the last 10 years, requiring no therapy for dermatomyositis. Fat loss was first noticed from the extremities by age 12 years, and it soon spread to involve the face and trunk. She did not have diabetes but has had hypertriglyceridemia for >15 years, which is being treated with gemfibrozil. She also had primary hypothyroidism requiring levothyroxine replacement. Physical examination revealed a height of 1.62 m, weight of 47.6 kg, and marked loss of SC adipose tissue from the face and extremities, including the palms and soles. SC fat was also decreased on the trunk except for the anterior abdomen, where it was still preserved. She had acanthosis nigricans over the axillae and neck and had mild hepatomegaly. A few irregular, hard calcified deposits were also palpable in the muscles of her arm, forearm, and abdomen. Her pooled serum leptin concentration was 2.35 ng/ml.

Patient 3 was a 15-year-old white boy from Kazakhstan who had AGL. Loss of SC fat was first noticed around the age of 5 years, whereas diabetes and hypertriglyceridemia were detected at age 10 years. Both these conditions were managed by diet therapy alone. He also had a congenital bicuspid aortic valve but was asymptomatic. Physical examination revealed a height of 1.82 m, weight of 39.6 kg, and marked loss of SC adipose tissue from the face, trunk, and extremities, including the palms and soles. There was no acanthosis nigricans. The liver was palpable 5 cm below the right costal margin. His pooled serum leptin level was 0.07 ng/ml.

Study design
The details of the study design have been published earlier (3). Patients were admitted to the General Clinical Research Center at University of Texas Southwestern Medical Center, Dallas, for initial evaluation before recombinant human leptin treatment and subsequently after 2, 4, and 8 months of recombinant human leptin therapy. However, patient 3 was evaluated at 3, 6, and 10 months after the baseline evaluation. Except for hypoglycemic drugs, which were tapered or discontinued as needed, none of their other concomitant medications were changed during the study period.

Human recombinant leptin was provided by Amgen, Inc. (Thousand Oaks, CA). It was administered subcutaneously every 12 h to achieve near-physiological concentrations of plasma leptin. The physiological replacement dose was estimated to be 0.04 mg · kg^-1 · day^-1 for women and 0.03 mg · kg^-1 · day^-1 for men. Patients were treated with 50% of the replacement dose for the first month, 100% during the second month, and 200% subsequently.

Measurement of insulin sensitivity
A high-dose insulin tolerance test using 0.2 IU/kg regular insulin (Novolin R; Novo Nordisk, Princeton, NJ) was performed on all the patients to assess insulin sensitivity at baseline and periodically during 2–10 months of leptin therapy as described earlier (3). Further, in patients 2 and 3, we performed euglycemic-hyperinsulinemic glucose clamp studies at baseline and after leptin therapy (4 months of leptin therapy in patient 2 and 10 months in patient 3) using an insulin infusion rate of 80 mU · m^-2 · min^-1 for 120 min according to the protocol described earlier (22).

¹H magnetic resonance spectroscopy
We performed ¹H magnetic resonance spectroscopy studies during the baseline period and at 2, 4, and 8 months after starting leptin therapy in patients 1 and 2, at baseline, and at 6 and 10 months after leptin therapy in patient 3. All measurements were performed at least 4 h postprandially with the patients lying supine. The details of the technique used have been described earlier (16). Briefly, image-guided proton-localized ¹H magnetic resonance spectroscopy and high-resolution T1-weighted imaging were performed on a 1.5 T Gyroscan NT whole body system (Philips Medical Systems, Best, the Netherlands) with the following imaging parameters: repetition time of 500 ms, echo time of 33 ms for the muscle and 40 ms for the liver, and 1,024 data points over a 1,000-kHz spectral width. Volumes of interest (voxel) within muscle were centered over the mid-soleus (12–15 mm [3]) and on the right lobe of the liver (30–50 mm [3]), taking care to avoid vascular structures and gross adipose tissue deposits and to ensure consistent orientation of muscle fibers along the magnetic field. Spectra were processed and resonances quantified using a standard analysis package (NUTS; ACORNNMR, Fremont, CA). The intramyocellular and intrahepatic lipid concentration is expressed as a percentage of the intensity of the water resonance peak.

	RESULTS

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The baseline characteristics of patients 1 and 2 and the effect of 4 months of leptin replacement on their physical and metabolic parameters have been described previously (3). Briefly, in patient 1, leptin replacement resulted in a weight loss of 3 kg, a decrease in HbA_1c concentration from 9.5 to 7.3%, and a reduction in fasting serum triglycerides from 11.23 to 2.09 mmol/l. Her serum leptin levels increased from 0.73 to 3.3 ng/ml. Similarly in patient 2, the body weight decreased from 47.6 kg at baseline to 45.6 kg at 4 months. Her HbA_1c concentration did not change, whereas fasting serum triglycerides decreased slightly from 5.05 mmol/l at baseline to 4.79 mmol/l at 4 months. Serum leptin levels increased from 2.35 to 8.5 ng/ml. Continued leptin therapy has caused further improvements in the metabolic parameters in both the patients at the end of 8 months. Similarly, 10 months of leptin therapy in patient 3 resulted in normalization of fasting plasma glucose from 11.6 to 4.5 mmol/l. Likewise, his HbA_1c declined from 10.7 to 6.7%, and fasting serum triglycerides declined from 9.14 to 1.74 mmol/l. During this period, his body weight increased slightly from 39.6 to 40.2 kg.

Leptin replacement led to improvement in whole-body insulin sensitivity in all three patients. After 8–10 months of leptin therapy, the rate of glucose disappearance during the insulin tolerance test, expressed as the K value, increased from 0.44 to 3.1% in patient 1, from 1.58 to 1.67% in patient 2, and from 0.66 to 1.36% in patient 3 (Fig. 1C). Hyperinsulinemic-euglycemic glucose clamp studies on patient 2 revealed an increase in the mean 60- to 120-min insulin-stimulated glucose uptake (M value) from 3.41 mg · kg^-1 · min^-1 at baseline to 3.73 mg · kg^-1 · min^-1 after 4 months of leptin therapy. Similar mean serum insulin levels were achieved during the hyperinsulinemic phase of the clamp studies (548 pmol/l during the baseline period and 616 pmol/l at 4 months). Mean fasting serum insulin level reduced from 78 to 41 pmol/l after 4 months of leptin therapy. In patient 3, the M value increased from 0.45 mg · kg^-1 · min^-1 at baseline to 3.72 mg · kg^-1 · min^-1 after 10 months of leptin therapy. The mean serum insulin levels achieved during the hyperinsulinemic phase of the clamp studies were 1,008 pmol/l during the baseline period and 1,151 pmol/l at 10 months. The fasting serum insulin level had decreased from 316 pmol/l at baseline to 119 pmol/l at 10 months.

View larger version (12K): [in this window] [in a new window]   Figure 1— Changes in intrahepatic (A) and intramyocellular (B) lipid content in three patients with generalized lipodystrophy treated with human recombinant leptin for 8–10 months. The corresponding changes in insulin sensitivity, measured as the rate of glucose disappearance during the insulin tolerance test (K value) are shown in C.

Figure 2 shows a transaxial T1-weighted magnetic resonance image of the calf in patients 1 and 2, indicating the position of the voxels. Striking absence of SC adipose tissue can be noted in both the patients. Lack of bone marrow fat and intermuscular fat is apparent in patient 1 with CGL, whereas these compartments are well preserved in patient 2. Changes in IMCL content with leptin therapy are shown in Fig. 1B. In patient 1, IMCL decreased from 2.1% at baseline to 0.8% at the end of 8 months; in patient 2, it declined from 1.4 to 1.0%, and in patient 3 from 1.1 to 0.7%.

View larger version (68K): [in this window] [in a new window]   Figure 2— T1-weighted transaxial magnetic resonance image of the calf in patient 1 (A) and patient 2 (B) showing position of the voxels over the soleus muscle. SC adipose tissue is markedly reduced in both the patients, whereas bone marrow fat and fat in the intermuscular fasciae are absent only in patient 1, who has CGL. L, left side.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS ADDENDUM References

Experience with leptin therapy in humans is limited. Leptin has previously been administered to a 9-year-old girl with congenital leptin deficiency (23) and to normal lean and obese adults for weight loss (24). Leptin therapy for 12 months in the girl with congenital leptin deficiency caused a weight loss of 16.4 kg, with fat loss accounting for 95% of it. There were, however, no changes in fasting serum glucose, insulin, or triglyceride levels with leptin therapy (23). Similarly, Heymsfield et al. (24) reported a dose-dependent weight loss (predominantly fat loss) ranging from 0.4 to 1.9 kg with escalating doses of leptin in 54 lean and 73 obese subjects. The investigators reported no changes in serum glucose or insulin profiles during the oral glucose tolerance test with leptin therapy. Both of these studies, however, did not examine intrahepatic or IMCL content.

Leptin has been found to be efficacious in reducing intrahepatic lipid concentration in mouse models of lipodystrophy as well as obesity. Marked hepatic steatosis in lipodystrophic mice can be reversed by leptin administration (5,7) or by transgenic overexpression of leptin (7). Furthermore, liver-specific overexpression of wild-type leptin receptors in Zucker diabetic fatty (ZDF fa/fa) rats (which have a loss of function mutation in leptin receptors) reduced excessive triglyceride accumulation in the liver (25). There are no data, however, on effects of leptin on IMCL content in mouse models.

The mechanism of leptin’s seemingly "liporegulatory" role is not known, but leptin presumably directly affects either lipid oxidation or synthesis. Using microarray expression profiles, Ferrante et al. (26) showed that leptin altered expression of a wide variety of genes involved in fatty acid metabolism in the livers of leptin-deficient ob/ob mice, including reduced suppression of insulin-induced protein 2, which may have a role in fatty acid overproduction. However, Lee et al. (25) suggest that the anti-steatotic action of leptin in the liver is due to enhanced fatty acid oxidation. They noted increased expression of peroxisome proliferator–activated receptor- and carnitine-palmitoyl transferase 1 in the livers of normal rats on a high-fat diet, which they ascribed to the effect of hyperleptinemia. Based on these observations, they conclude that the physiological role of hyperleptinemia secondary to energy excess is to protect non–adipocytes from steatosis and lipotoxicity.

As previously mentioned, various cross-sectional studies have identified IMCL content as an important determinant of whole-body insulin sensitivity (9–12). Furthermore, IMCL concentrations decrease with exercise and weight loss, interventions that also improve insulin sensitivity (27–29). However, recent reports of increased IMCL content in endurance-trained athletes who are extremely insulin sensitive present a paradox (30). It has been suggested that the capacity for lipid oxidation may be a more important mediator of the association between excess muscle lipid accumulation and insulin resistance. Interestingly, leptin stimulates fatty acid oxidation in skeletal muscle by activating AMP-activated protein kinase and inhibiting acetyl CoA carboxylase (31). It is therefore conceivable that a leptin-induced increase in fatty acid oxidation caused a reduction in IMCL accumulation and an improvement in peripheral insulin sensitivity in our patients with lipodystrophy. Even though we noticed an overall reduction in IMCL content with leptin therapy, there were small transient increases in IMCL during the study, whereas reductions in intrahepatic lipid content were more pronounced, consistent, and progressive with the duration of leptin therapy. It is not clear whether these differences are related to methodological difficulties associated with separation of intra- and extramyocellular lipid spectra or to the dynamics of lipid oxidation and storage with changing insulin sensitivity.

We conclude that leptin replacement in hypoleptinemic patients with generalized lipodystrophy decreased intrahepatic and IMCL content, which may partly explain improvement in insulin sensitivity with leptin therapy.

	ADDENDUM

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Since the submission of this manuscript, similar results have been reported by Petersen et al. (J Clin Invest 109:1345–1350, 2002) in three women with generalized lipodystrophy. The authors reported an 86% reduction in hepatic triglyceride content and a 33% reduction in muscle triglyceride content after 3–8 months of leptin therapy using the same treatment protocol as ours.

	Acknowledgments

 
This study was supported in part by National Institutes of Health Grants R01-DK54387 and M01-RR00633 and grants from the Southwest Medical Foundation and Amgen, Inc.

We are grateful to Angela Osborn for technical assistance, Angela Soto for help with preparation of the manuscript, and the nursing and dietetic services of the General Clinical Research Center for providing care to the patients.

	Footnotes

 
Address correspondence and reprint requests to Abhimanyu Garg, MD, Chief, Division of Nutrition and Metabolic Diseases, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Y3-222, Dallas, TX 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.

Received for publication 1 March 2002 and accepted in revised form 28 September 2002.

A.J.W. and A.M.D. hold stock in Amgen, Inc.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

	References

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS ADDENDUM References

 

1. Garg A: Lipodystrophies. Am J Med 108:143–152, 2000[Medline]
   
2. Pardini VC, Victoria IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB, Milagres G, Purisch S, Velho G: Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab 83:503–508, 1998[Abstract/Free Full Text]
   
3. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578, 2002[Abstract/Free Full Text]
   
4. Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C: Life without white fat: a transgenic mouse. Genes Dev 12:3168–3181, 1998[Abstract/Free Full Text]
   
5. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76, 1999[Medline]
   
6. Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML: Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 105:271–278, 2000[Medline]
   
7. Ebihara K, Ogawa Y, Masuzaki H, Shintani M, Miyanaga F, Aizawa-Abe M, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Gavrilova O, Reitman ML, Nakao K: Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50:1440–1448, 2001[Abstract/Free Full Text]
   
8. Stein DT, Dobbins RL, Szczepaniak LS, Malloy C, McGarry JD: Skeletal muscle triglyceride stores are increased in insulin resistance. Diabetes 46(Suppl. 1):23A, 1997
   
9. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI: Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113–116, 1999 (errata appears in Diabetologia 42:386, 1999 and Diabetologia 42:1269, 1999)[Medline]
   
10. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Haring HU: Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 48:1113–1119, 1999[Abstract]
    
11. Forouhi NG, Jenkinson G, Thomas EL, Mullick S, Mierisova S, Bhonsle U, McKeigue PM, Bell JD: Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men. Diabetologia 42:932–935, 1999[Medline]
    
12. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen AM, Yki-Jarvinen H: Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 50:2337–2343, 2001[Abstract/Free Full Text]
    
13. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N: Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107:450–455, 1999[Medline]
    
14. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H: Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758, 2000[Abstract]
    
15. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850, 2001[Abstract/Free Full Text]
    
16. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT: Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 276:E977–E989, 1999
    
17. Case records of the Massachusetts General Hospital: weekly clinicopathologic exercises. Case 1-1975. N Engl J Med 292:35–41, 1975[Medline]
    
18. Brechtel K, Jacob S, Machann J, Hauer B, Nielsen M, Meissner HP, Matthaei S, Haering HU, Claussen CD, Schick F: Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS. J Magn Reson Imaging 12:306–310, 2000[Medline]
    
19. Garg A, Fleckenstein JL, Peshock RM, Grundy SM: Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 75:358–361, 1992[Abstract]
    
20. Fleckenstein JL, Garg A, Bonte FJ, Vuitch MF, Peshock RM: The skeleton in congenital, generalized lipodystrophy: evaluation using whole-body radiographic surveys, magnetic resonance imaging and technetium-99m bone scintigraphy. Skeletal Radiol 21:381–386, 1992[Medline]
    
21. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23, 2002[Medline]
    
22. Abate N, Garg A, Peshock R, Stray-Gundersen J, Grundy SM: Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest 96:88–98, 1995
    
23. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884, 1999[Free Full Text]
    
24. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575, 1999[Abstract/Free Full Text]
    
25. Lee Y, Wang MY, Kakuma T, Wang ZW, Babcock E, McCorkle K, Higa M, Zhou YT, Unger RH: Liporegulation in diet-induced obesity: the antisteatotic role of hyperleptinemia. J Biol Chem 276:5629–5635, 2001[Abstract/Free Full Text]
    
26. Ferrante AW Jr, Thearle M, Liao T, Leibel RL: Effects of leptin deficiency and short-term repletion on hepatic gene expression in genetically obese mice. Diabetes 50:2268–2278, 2001[Abstract/Free Full Text]
    
27. Decombaz J, Fleith M, Hoppeler H, Kreis R, Boesch C: Effect of diet on the replenishment of intramyocellular lipids after exercise. Eur J Nutr 39:244–247, 2000[Medline]
    
28. Goodpaster BH, Theriault R, Watkins SC, Kelley DE: Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism 49:467–472, 2000[Medline]
    
29. Malenfant P, Tremblay A, Doucet E, Imbeault P, Simoneau JA, Joanisse DR: Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training. Am J Physiol Endocrinol Metab 280:E632–E639, 2001[Abstract/Free Full Text]
    
30. Goodpaster BH, He J, Watkins S, Kelley DE: Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755–5761, 2001[Abstract/Free Full Text]
    
31. Minokoshi Y, Km Y-B, Peroni OD, Fryer LGD, Muller C, Carling D, Kahn BB: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343, 2002[Medline]
    

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				W. Huang, N. Dedousis, B. A. Bhatt, and R. M. O'Doherty Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity J. Biol. Chem., May 21, 2004; 279(21): 21695 - 21700. [Abstract] [Full Text] [PDF]

				A. Garg Acquired and Inherited Lipodystrophies N. Engl. J. Med., March 18, 2004; 350(12): 1220 - 1234. [Full Text] [PDF]

				P. J. Havel Update on Adipocyte Hormones: Regulation of Energy Balance and Carbohydrate/Lipid Metabolism Diabetes, February 1, 2004; 53(90001): S143 - 151. [Abstract] [Full Text]

				L. K Heilbronn and E. Ravussin Calorie restriction and aging: review of the literature and implications for studies in humans Am. J. Clinical Nutrition, September 1, 2003; 78(3): 361 - 369. [Abstract] [Full Text] [PDF]

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