Elif Arioglu Oral, M.D., Vinaya Simha, M.D., Elaine Ruiz, N.P., Alexa Andewelt, B.S., Ahalya Premkumar, M.D., Peter Snell, Ph.D., Anthony J. Wagner, Ph.D., Alex M. DePaoli, M.D., Marc L. Reitman, M.D., Ph.D., Simeon I. Taylor, M.D., Ph.D., Phillip Gorden, M.D., and Abhimanyu Garg, M.D.
Background The adipocyte hormone leptin is important in regulatingenergy homeostasis. Since severe lipodystrophy is associatedwith leptin deficiency, insulin resistance, hypertriglyceridemia,and hepatic steatosis, we assessed whether leptin replacementwould ameliorate this condition.
Methods Nine female patients (age range, 15 to 42 years; eightwith diabetes mellitus) who had lipodystrophy and serum leptinlevels of less than 4 ng per milliliter (0.32 nmol per milliliter)received recombinant methionyl human leptin (recombinant leptin).Recombinant leptin was administered subcutaneously twice a dayfor four months at escalating doses to achieve low, intermediate,and high physiologic replacement levels of leptin.
Results During treatment with recombinant leptin, the serumleptin level increased from a mean (±SE) of 1.3±0.3ng per milliliter to 11.1±2.5 ng per milliliter (0.1±0.02to 0.9±0.2 nmol per milliliter). The absolute decreasein the glycosylated hemoglobin value was 1.9 percent (95 percentconfidence interval, 1.1 to 2.7 percent; P=0.001) in the eightpatients with diabetes. Four months of therapy decreased averagetriglyceride levels by 60 percent (95 percent confidence interval,43 to 77 percent; P<0.001) and liver volume by an averageof 28 percent (95 percent confidence interval, 20 to 36 percent;P=0.002) in all nine patients and led to the discontinuationof or a large reduction in antidiabetes therapy. Self-reporteddaily caloric intake and the measured resting metabolic ratealso decreased significantly with therapy. Overall, recombinantleptin therapy was well tolerated.
Conclusions Leptin-replacement therapy improved glycemic controland decreased triglyceride levels in patients with lipodystrophyand leptin deficiency. Leptin deficiency contributes to theinsulin resistance and other metabolic abnormalities associatedwith severe lipodystrophy.
The adipocyte hormone leptin has a central role in energy homeostasis.1Serum leptin levels are directly proportional to adipocyte mass.2Normally, a low leptin level signals starvation and directsthe body to adapt to this condition.3 One way to gain insightinto the physiological importance of leptin in humans is tostudy the conditions associated with its absence or deficiency.
Patients with a complete deficiency of leptin as a result ofmutations in the leptin gene are morbidly obese from infancyand have a number of hormonal abnormalities, including insulinresistance and hypogonadotropic hypogonadism.4 Physiologic replacementwith recombinant leptin for one year in one such patient ledto a substantial weight reduction and an improvement in thehormonal abnormalities.5
Severe lipodystrophy, caused by a deficiency or destructionof adipose cells, is another state characterized by low leptinlevels.6 Other abnormalities in this condition include hypertriglyceridemiaand severe insulin resistance, which is usually accompaniedby diabetes mellitus.6,7 There are several genetic and acquiredforms of lipodystrophy in humans, and studies of a variety ofgenetically engineered animal models6,8 demonstrated that themetabolic abnormalities develop as a consequence of fat loss.9Why is adipose tissue so vital to the prevention of the metabolicabnormalities? One hypothesis is that the adipocyte hormoneleptin has a critical role in preventing the insulin resistanceand hypertriglyceridemia of lipodystrophy. Interestingly, leptin-replacementtherapy at a level meant to achieve physiologic levels led toa dramatic improvement in insulin resistance, hyperglycemia,hypertriglyceridemia, and hepatic steatosis in a mouse modelof lipodystrophy.10 Therefore, we sought to determine whethersuch treatment would improve the insulin resistance, diabetes,and hypertriglyceridemia of patients with lipodystrophy.
Methods
Patients
Eligible patients had to have low serum leptin levels (lessthan 3 ng per milliliter [0.24 nmol per milliliter] in the caseof male patients and less than 4 ng per milliliter [0.32 nmolper milliliter] in the case of female patients) in associationwith lipodystrophy and at least one of the following metabolicabnormalities: diabetes mellitus, defined according to the criteriaof the American Diabetes Association11; serum triglyceride levels(measured after an overnight fast) of more than 200 mg per deciliter(2.23 mmol per liter); and fasting serum insulin levels of morethan 30 µU per milliliter (215 pmol per liter). Table 1summarizes the base-line clinical characteristics of the ninepatients treated in the study. The patients ranged from 15 to42 years of age. All nine were female, although the study wasopen to both sexes. Five of the nine patients had congenitalgeneralized lipodystrophy, or the Seip–Berardinelli syndrome,characterized by generalized fat loss from birth in associationwith other clinical criteria (Online Mendelian Inheritance inMan [OMIM]13 number 269700).14 One patient had Dunnigan's familialpartial lipodystrophy (OMIM13 number 151660).15,16 The otherthree patients had acquired generalized lipodystrophy.
Table 1. Base-Line Characteristics of the Patients and Treatment Regimens at Base Line and after Four Months of Recombinant Leptin.
Study Design
The study was designed as a prospective, open-label study atthe Diabetes Branch of the National Institute of Diabetes andDigestive and Kidney Diseases of the National Institutes ofHealth (NIH) and the University of Texas Southwestern MedicalCenter in Dallas. Amgen (Thousand Oaks, Calif.) provided recombinantmethionyl human leptin (recombinant leptin). Although Amgenprovided the recombinant leptin, the data were held by the academicinvestigators. The response of each patient was compared withher base-line values. Because of the rarity and clinical variabilityof lipodystrophy syndromes, it was not feasible to include arandomized, placebo-treated control group. The study was approvedby the institutional review boards of the study centers, andwritten informed consent was obtained from all patients. Thestudy was initiated in August 2000, and data collection wascompleted at the end of June 2001.
The patients were evaluated as inpatients before treatment andagain after one, two, and four months of recombinant leptintherapy. All patients had been receiving stable doses of othermedications for at least six weeks (range, six weeks to eightmonths) before they began to receive leptin-replacement therapy.During the study, the doses of hypoglycemic drugs were taperedor the treatments discontinued as needed (Table 1).
Recombinant leptin was administered subcutaneously every 12hours. The physiologic replacement dose was estimated to be0.03 mg per kilogram of body weight per day for girls under18 years of age and 0.04 mg per kilogram per day for women onthe basis of information provided by the manufacturer. Thesedoses are approximately 1/10 of the dose most commonly usedin obesity trials. Patients were treated with 50 percent ofthe replacement dose for the first month, 100 percent for thesecond month, and 200 percent for the third and fourth months.
Biochemical Analyses
Serum glucose and triglyceride levels were determined accordingto standard methods with the use of automated equipment (Hitachi,Boehringer Mannheim, Indianapolis) at the NIH and a Beckmaninstrument (Fullerton, Calif.) at the University of Texas SouthwesternMedical Center. Glycosylated hemoglobin values were measuredby ion-exchange high-performance liquid chromatography (Bio-RadLaboratories, Hercules, Calif.), and levels of free fatty acidswere measured with use of a commercial kit (Wako, Richmond,Va.). Serum insulin levels were determined by immunoassays withthe use of reagents provided by Abbott Instruments (Abbott Park,Ill.) at the NIH and a commercial kit (Linco Research, St. Charles,Mo.) at the University of Texas Southwestern Medical Center.Serum leptin levels were determined by immunoassays with theuse of a commercial kit (Linco Research).
Procedures
The resting metabolic rate was measured (Deltatrac equipment,Sensormedics, Yorba Linda, Calif.) between 6 a.m. and 8 a.m.while patients rested, after an overnight fast of more thaneight hours. After an overnight fast, each patient underwentan oral glucose-tolerance test in which 75 g of dextrose wasadministered orally.
A high-dose insulin-tolerance test was performed with the useof 0.2 U of regular insulin per kilogram to assess the patients'sensitivity to insulin. The K constant (the rate of glucosedisappearance as a reflection of the body's overall sensitivityto insulin) was calculated as the rate constant for the decreasein blood glucose levels after the intravenous administrationof insulin with the use of first-order kinetics.17 The sevenpatients who were seen at the NIH Clinical Center reported theirdaily food intake at base line and at four months using a standardizedquestionnaire.18
Body fat was determined with use of a dual-energy x-ray absorptiometer(model QDR 4500, Hologic, Bedford, Mass.).19 Axial T1-weightedmagnetic resonance imaging of the liver was performed with useof a 1.5-T scanner (General Electric Medical Systems, Milwaukee,at the NIH and Philips Medical Systems, Best, the Netherlands,at the University of Texas Southwestern Medical Center).20 Livervolumes were calculated with use of the MEDx image-analysissoftware package (Sensor Systems, Sterling, Va.).
Statistical Analysis
Values are presented as means ±SE. We used an analysisof variance with repeated measures to compare the study variablesduring various study periods. Skewed data on triglyceride levelsand calculated K constants were log-transformed. We used a pairedt-test wherever it was applicable to compare base-line datawith data obtained at various times. We analyzed changes inplasma glucose levels during the oral glucose-tolerance testusing a two-factor analysis of variance in which the study periodand the time during the test were modeled as repeated factors.We calculated 95 percent confidence intervals for the differencesbetween the means according to the method of Hahn and Meeker.21The manuscript was jointly written by a committee of the investigators.
Results
Base-Line Characteristics of the Patients
Eight of the nine patients in the study had diabetes (Table 1),and all nine had hyperlipidemia (Table 2). All patientswith diabetes were receiving medications for their diabetesbefore the study began, and four of the nine patients receivedlipid-lowering therapy (Table 1). Their average glycosylatedhemoglobin value was 9.1±0.5 percent (normal, less than5.6 percent) at the base-line evaluation. The mean triglyceridelevels were elevated at base line, at 1405 mg per deciliter(16 mmol per liter) (range, 322 to 7420 mg per deciliter [3.6to 83.8 mmol per liter]; normal range, 35 to 155 mg per deciliter[0.4 to 1.7 mmol per liter]). Free fatty acid levels were alsoincreased, at a mean of 1540±407 µmol per liter(normal, 350 to 550).
Table 2. Metabolic Values before and during Treatment with Recombinant Leptin.
Changes in Circulating Leptin Levels
The mean serum leptin level was 1.3±0.3 ng per milliliter(0.1±0.02 nmol per milliliter) at base line (Table 1)and increased to 2.3±0.5 ng per milliliter (0.2±0.04nmol per milliliter) at the end of the first month of therapy,to 5.5±1.2 ng per milliliter (0.4±0.1 nmol permilliliter) at the end of the second month, and to 11.1±2.5ng per milliliter (0.9±0.2 nmol per milliliter) at theend of the fourth month. Thus, the administration of recombinantleptin resulted in approximately normal serum leptin levelsin these patients.12
Changes in Metabolic Control
The first patient treated in this study (Patient 1) was alsothe most severely affected,22 and her clinical course is shownin Figure 1. Leptin-replacement therapy had a marked effectin this patient and in the group as a whole.22 Before the initiationof leptin therapy, the eight patients with diabetes had poormetabolic control, with a mean glycosylated hemoglobin valueof 9.1±0.5 percent. After four months of leptin-replacementtherapy, the glycosylated hemoglobin value decreased by a meanof 1.9 percentage points (95 percent confidence interval, 1.1to 2.7; P=0.001). The individual responses of the patients areprovided in Table 2. Glycemic control improved despite the factthat antidiabetic therapy was decreased or discontinued duringthe four months of leptin-replacement therapy (Table 1).
Figure 1. Clinical Course of Patient 1, as Assessed by Changes in Mean Triglyceride Levels, Glycosylated Hemoglobin Values, and Serum Leptin Values.
Patient 1 was healthy at birth but began to lose fat between the ages of 10 and 12 years. Severe hypertriglyceridemia developed at the age of 13 years, and diabetes at the age of 14 years. When she presented to the NIH Clinical Center at the age of 15 years, her triglyceride levels consistently exceeded 10,000 mg per deciliter (113 mmol per liter) and her glycosylated hemoglobin value was 9.5 percent. She had painful eruptive cutaneous xanthomata all over her body and massive hepatomegaly, extending to the pelvic brim. Weekly plasmapheresis therapy and orlistat were added to alleviate hypertriglyceridemia (Panel A).22 Over a four-month period, treatment with recombinant leptin caused a marked, progressive improvement in hypertriglyceridemia and hyperglycemia that allowed plasmapheresis and medications for diabetes to be discontinued. The improvements in metabolic values were accompanied by the disappearance of cutaneous xanthomata. In addition, the liver volume decreased by nearly 40 percent, from 4213 ml to 2644 ml (Panel B; both scans are at the same level and scale). To convert triglyceride values to millimoles per liter, multiply by 0.01129. To convert leptin values to nanomoles per milliliter, multiply by 0.08.
At the end of four months of recombinant leptin therapy, thefasting triglyceride levels had fallen by 60 percent (95 percentconfidence interval, 43 to 77 percent; P<0.001). The individualresponses of the patients are given in Table 2. During the sameperiod, fasting levels of free fatty acids fell from a meanof 1540±407 µmol per liter to 790±164 µmolper liter (P=0.05).
The insulin-tolerance test showed that plasma glucose levelshad significantly decreased at the end of four months of therapy(Figure 2A). The K constant (the rate of glucose disappearance)increased from 0.007±0.001 to 0.017±0.004, indicatingan improvement in whole-body sensitivity to insulin (P=0.04).Furthermore, the glucose levels measured in response to an oralglucose load (75 g of dextrose) were significantly lower thanthe base-line levels (Figure 2B).
Figure 2. Mean (±SE) Plasma Glucose Levels in Response to an Insulin-Tolerance Test (Panel A) and an Oral Glucose-Tolerance Test (Panel B) in Nine Patients at Base Line and after Four Months of Leptin-Replacement Therapy.
Leptin improved the glucose curves during both the insulin-tolerance test and the oral glucose-tolerance test. In Panel A, plasma glucose levels were measured before and after the intravenous administration of 0.2 U of insulin per kilogram before and after four months of leptin-replacement therapy. Asterisks indicate a significant difference (P<0.02) between groups. In Panel B, plasma glucose levels were measured during an oral glucose-tolerance test with 75 g of dextrose before and after four months of leptin-replacement therapy. Asterisks indicate a significant difference (P<0.01) between groups. To convert glucose values to millimoles per liter, multiply by 0.0551.
Since all patients derived clinically significant benefit fromleptin-replacement therapy, all continue to receive treatment.
Changes in Liver Volume and Liver-Function Tests
At base line, the mean liver volume was 3097±391 ml (approximatelyfour times the volume in age- and sex-matched persons of normalweight). Leptin decreased the liver volume by an average of28 percent (95 percent confidence interval, 20 to 36 percent)from base line (P=0.002). The decrease in liver size was associatedwith an improvement in liver-function tests. Base-line alanineaminotransferase levels had decreased from 66±16 to 24±4U per liter at the end of four months of therapy (P=0.02). Likewise,serum aspartate aminotransferase levels were 53±12 Uper liter at base line and 21±2 U per liter at the endof four months of therapy (P=0.03).
Changes in Energy Balance
Data on self-reported daily caloric intake were available forseven patients. The daily caloric intake decreased from a meanof 2680±250 kcal per day at base line to 1600±150kcal per day after four months of leptin-replacement therapy(P=0.005). There was a parallel decrease in the resting metabolicrate (measured in all nine patients), from 1920±150 to1580±80 kcal per day (P=0.003).
All but one patient (Patient 3) had lost weight at the end offour months of treatment (mean weight loss, 3.6±0.9 kg;range, –1.7 to 7.3). An important fraction of the weightloss (50 to 65 percent) was attributed to the decrease in livervolume.
Adverse Events
Patient 1 had a severe episode of nausea and vomiting afterthe first dose of recombinant leptin. After the second dose,Patient 6 had an exacerbation of hypertension associated withflushing. Patient 7 was hospitalized for a streptococcal infectionduring the third month of therapy. All these events resolved,and none recurred with the continuation of therapy. No skinreactions at injection sites were reported or observed.
Withdrawal of Recombinant Leptin
Since the patients had reduced their intake of food during leptin-replacementtherapy, we assessed whether the metabolic values were maintainedin the presence of a reduced intake of food. Patient 1 was admittedto the NIH Clinical Center and received 1900 kcal per day (55percent carbohydrates, 25 percent fat, and 20 percent protein),which was based on the patient's reported intake of food duringleptin-replacement therapy and on a measurement of the restingmetabolic rate, in the form of three meals and two snacks. Leptin-replacementtherapy was stopped after day 5. Plasma glucose levels weremeasured before each meal and at bedtime, and the daily averageswere calculated. Fasting plasma triglyceride and insulin levelswere determined. Within 48 hours after the withdrawal of recombinantleptin, the fasting plasma triglyceride and insulin levels beganto increase. The effects were corrected by the resumption ofleptin-replacement therapy (Figure 3).
Figure 3. Effects of Leptin-Replacement Therapy on Insulin Sensitivity and Triglyceride Levels in Patient 1 while She Was Following a Diet Containing 1900 kcal per Day.
The effects of leptin-replacement therapy appeared to be independent of the decrease in food intake. Patient 1 was hospitalized and given a diet containing 1900 kcal per day (according to the estimated intake of food while she was receiving 0.08 mg of recombinant leptin per kilogram per day). Recombinant leptin was withdrawn at the end of day 5 while all other medications were kept constant. Fasting plasma insulin levels (normal range, 5 to 15 µU per milliliter [36 to 107 pmol per liter]), fasting plasma triglyceride levels (normal range, 35 to 155 mg per deciliter [0.4 to 1.7 mmol per liter]), and mean daily glucose levels are shown. Leptin-replacement therapy was resumed on day 15, when nausea, vomiting, and abdominal pain developed consistent with the presence of pancreatitis. The asterisk refers to the 24-hour period of pancreatitis during which there was no oral intake. To convert triglyceride values to millimoles per liter, multiply by 0.01129. To convert glucose values to millimoles per liter, multiply by 0.0551. To convert insulin values to picomoles per liter, multiply by 7.15.
Discussion
Leptin-replacement therapy led to clear and dramatic metabolicbenefits in this group of nine patients with lipodystrophy andleptin deficiency. Treatment with recombinant leptin resultedin an absolute reduction in the glycosylated hemoglobin valueof 1.9 percent. Such a reduction is predicted to decrease therelative risk of retinopathy by approximately 48 percent andnephropathy by approximately 22 percent in the diabetic population.23Furthermore, triglyceride levels fell by 60 percent, and sucha reduction is predicted to decrease the relative risk of cardiovascularevents in the general population by 35 to 65 percent.24,25
To date, the insulin resistance and hypertriglyceridemia thatcharacterize lipodystrophy have been refractory to treatment.26Thiazolidinediones appear to be the most effective therapy,albeit an imperfect one.27 Commonly, this condition is managedwith a combination of medications, including high doses of insulin,oral hypoglycemic agents (e.g., metformin and thiazolidinediones),and lipid-lowering drugs (e.g., fibrates and statins). Despitesuch therapy, patients continue to have severe hypertriglyceridemia,leading to recurrent attacks of acute pancreatitis; severe hyperglycemia,posing risks of diabetic retinopathy and nephropathy; and nonalcoholicsteatohepatitis, which can result in cirrhosis. Leptin-replacementtherapy appears to have the potential to prevent all these complications.
Our results also demonstrate a novel action of leptin. Leptinappears to provide a signal that regulates total-body sensitivityto insulin and triglyceride levels in addition to its knownrole in the control of energy homeostasis.
Although our study was not randomized, the improved metaboliccontrol appeared to be due to leptin-replacement therapy ratherthan to an improvement in general compliance associated withparticipation in a study.
An important unanswered question is the effect of decreasedfood intake on the changes in metabolic values in this study.In patients with lipodystrophy, limiting caloric intake improvesglucose and lipid abnormalities.28 Leptin-replacement therapyreduced food intake in our patients. However, in an analysisinvolving Patient 1, we observed an additional effect of leptin-replacementtherapy on insulin sensitivity and triglyceride metabolism thatwas independent of food intake. In this patient, fasting insulinand triglyceride levels increased within two and four days,respectively, after recombinant leptin was withdrawn even thoughthe level of food intake remained constant. Similar data havebeen reported in paired-feeding experiments (with or withoutleptin administration) involving lipoatrophic mice.10,29
Leptin has been identified as the missing hormone in obese (ob/ob)mice.1 In these mice, leptin-replacement therapy decreased foodintake and body weight.30,31,32 Because of such initial observations,obesity has been the focus of most therapeutic trials with leptin.However, most obese people have high serum leptin levels andare therefore presumed to have leptin resistance.33 Thus far,the average weight loss in obese persons has not been significant,34except in patients with congenital leptin deficiency.5
Study of various mouse models of lipodystrophy suggests thatthe absence of adipose tissue is the cause of insulin resistancein this syndrome.35,36,37 The demonstration that transplantationof adipose tissue into mice with lipodystrophy ameliorates insulinresistance and improves metabolic control provides strong supportfor this hypothesis.9 However, why adipose tissue was requiredto maintain whole-body sensitivity to insulin has remained unclear.Shimomura et al. tested the efficacy of leptin replacement ina mouse model and observed a dramatic improvement in glucoseand triglyceride levels and hepatic steatosis.10 Taken together,these observations and our results suggest that leptin controlsthe majority of the regulatory action of adipose tissue on whole-bodysensitivity to insulin.
In our study, leptin-replacement therapy was associated witha decline in the resting metabolic rate. This finding is parallelto observations in patients with a congenital absence of leptin.33Although the mechanism of this effect is unclear, we presumethat the leptin-induced decrease in food intake reduces diet-inducedthermogenesis.
Unger and colleagues have reported that leptin administrationin Zucker rats corrects steatosis in a variety of organs thatact as sites of lipid accumulation, such as the liver, isletcells, and the heart.38,39 The accumulation of lipids at thesesites may represent a spillover phenomenon resulting from thefact that adipocytes have reached their capacity to store triglycerides.In patients with lipodystrophy, these organs are the only sitesthat can store lipids. Leptin treatment of mice with lipodystrophycauses a dramatic decrease in hepatic stores of triglycerides.In parallel, leptin-replacement therapy in our patients withlipodystrophy caused a significant reduction in liver volume.
The concept that adipose tissue is an endocrine organ was stronglysupported by the discovery of leptin. Leptin has effects (director indirect) on the key organs of metabolism, including thebrain, liver, muscle, fat, and pancreas. Leptin is certainlynot the only circulating adipocyte signal.40,41,42 Lack of adipocytesshould result in a deficiency of all fat-derived signals. Onthe basis of our findings, leptin deficiency appears to be thechief contributor to the metabolic abnormalities associatedwith lipodystrophy. Thus, severe lipodystrophy may be an importantreason to consider leptin-replacement therapy. The optimal doseof recombinant leptin in patients with lipodystrophy, the roleof leptin-replacement therapy in treating other insulin-resistancestates, and the degree of leptin deficiency that will respondto leptin-replacement therapy remain to be determined.
Supported in part by grants from the NIH (RO1-DK54387 and MO1-RR00633)and from Amgen.
Drs. Wagner and DePaoli are employees of Amgen. Dr. Taylor isnow an employee of Eli Lilly.
We are indebted to the following for their contribution to thestudy: Oksana Gavrilova, Monica Skarulis, Karim Calis, BeverleyAdams-Huet, Jerry Payne, Bryan Fox, Nancy Sebring, Patti Riggs,Bernice Marcus-Samuels, Craig Cochran, Angela Osborn, EstherBergman, nurses and clinical fellows, and the Metabolic CartConsult Service.
Source Information
From the Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (E.A.O., E.R., A.A., M.L.R., S.I.T., P.G.), and the Clinical Center (A.P.), National Institutes of Health, Bethesda, Md.; the University of Texas Southwestern Medical Center at Dallas, Dallas (V.S., P.S., A.G.); and Amgen, Thousand Oaks, Calif. (A.J.W., A.M.D.).
Address reprint requests to Dr. Oral at the National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes Branch, Bldg. 10, Rm. 8D20, Bethesda, MD 20892-1770, or at elif_arioglu{at}nih.gov.
References
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;372:425-432. [Erratum, Nature 1995;374:479.] [CrossRef][Medline]
Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-295. [Free Full Text]
Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-252. [CrossRef][Medline]
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][Medline]
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. [Free Full Text]
Reitman ML, Arioglu E, Gavrilova O, Taylor SI. Lipoatrophy revisited. Trends Endocrinol Metab 2000;11:410-416. [CrossRef][ISI][Medline]
Lawrence RD. Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin. Lancet 1946;1:724-31, 773.
Magre J, Delepine M, Khallouf E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001;28:365-370. [CrossRef][ISI][Medline]
Gavrilova A, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000;105:271-278. [ISI][Medline]
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][Medline]
Peters AL, Schriger DL. The new diagnostic criteria for diabetes: the impact on management of diabetes and macrovascular risk factors. Am J Med 1998;105:Suppl 1A:15S-19S. [Medline]
Ruhl CE, Everhart JE. Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr 2001;74:295-301. [Free Full Text]
McKusick V. Online mendelian inheritance in man. Baltimore: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, 2001. (Accessed January 25, 2002, at http://www.ncbi.nlm.nih.gov/Omim.)
Garg A, Fleckenstein JL, Peshock RM, Grundy SM. Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 1992;75:358-361. [Abstract]
Garg A, Peshock RM, Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 1999;84:170-174. [Free Full Text]
Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000;9:109-112. [Free Full Text]
Harrison LC, Martin FI, Melick RA. Correlation between insulin receptor binding in isolated fat cells and insulin sensitivity in obese human subjects. J Clin Invest 1976;58:1435-1441. [ISI][Medline]
Feskanich D, Rimm EB, Giovannucci EL, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc 1993;93:790-796. [CrossRef][ISI][Medline]
Lambrinoudaki I, Georgiou E, Douskas G, Tsekes G, Kyriakidis M, Proukakis C. Body composition assessment by dual-energy x-ray absorptiometry: comparison of prone and supine measurements. Metabolism 1998;47:1379-1382. [CrossRef][Medline]
Abate N, Burns D, Peshock RM, Garg A, Grundy SM. Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers. J Lipid Res 1994;35:1490-1496. [Abstract]
Hahn GJ, Meeker WQ. Statistical intervals: a guide for practitioners. New York: John Wiley, 1991.
Bolan C, Arioglu Oral E, Gorden E, Taylor S, Lietman SF. Intensive, long-term plasma exchange therapy for severe hypertriglyceridemia in acquired generalized lipoatrophy. J Clin Endocrinol Metab 2002;87:380-384. [Free Full Text]
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33): UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853. [Erratum, Lancet 1999;354:602.] [CrossRef][ISI][Medline]
Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998;82:Suppl:67U-73U. [CrossRef][ISI][Medline]
Gotto AM Jr. Triglyceride as a risk factor for coronary artery disease. Am J Cardiol 1998;82:22Q-25Q. [ISI][Medline]
Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000;133:263-274. [Free Full Text]
Trygstad O, Seip M, Oseid S. Lipodystrophic diabetes treated with fenfluramine. Int J Obes 1977;1:287-292. [Medline]
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. [Free Full Text]
Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-549. [Free Full Text]
Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-546. [Free Full Text]
Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-543. [Free Full Text]
Mantzoros CS, Flier JS. Leptin as a therapeutic agent -- trials and tribulations. J Clin Endocrinol Metab 2000;85:4000-4002. [Free Full Text]
Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282:1568-1575. [Free Full Text]
Burant CF, Sreenan S, Hirano K, et al. Troglitazone action is independent of adipose tissue. J Clin Invest 1997;100:2900-2908. [ISI][Medline]
Moitra J, Mason MM, Olive M, et al. Life without white fat: a transgenic mouse. Genes Dev 1998;12:3168-3181. [Free Full Text]
Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998;12:3182-3194. [Free Full Text]
Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 1995;44:863-870. [Abstract]
Unger RH, Zhou YT, Orci L. Regulation of fatty acid homeostasisin cells: novel role of leptin. Proc Natl Acad Sci U S A 1999;96:2327-2332. [Free Full Text]
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][ISI][Medline]
Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001;98:2005-2010. [Free Full Text]
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947-953. [CrossRef][ISI][Medline]
Unger, R. H.
(2008). Noninvasive tracking of gene expression by reporter transgene imaging. Proc. Natl. Acad. Sci. USA
105: 12641-12642
[Full Text]
Yauger, B. J., Gorden, P., Park, J., Cochran, E., Stratton, P.
(2008). Effect of Depot Medroxyprogesterone Acetate on Glucose Tolerance in Generalized Lipodystrophy. Obstet Gynecol
112: 445-447
[Abstract][Full Text]
Karmazyn, M., Purdham, D. M., Rajapurohitam, V., Zeidan, A.
(2008). Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart. Cardiovasc Res
79: 279-286
[Abstract][Full Text]
Misra, A., Alappan, N. K., Vikram, N. K., Goel, K., Gupta, N., Mittal, K., Bhatt, S., Luthra, K.
(2008). Effect of Supervised Progressive Resistance-Exercise Training Protocol on Insulin Sensitivity, Glycemia, Lipids, and Body Composition in Asian Indians With Type 2 Diabetes. Diabetes Care
31: 1282-1287
[Abstract][Full Text]
Koh, K. K., Park, S. M., Quon, M. J.
(2008). Leptin and Cardiovascular Disease: Response to Therapeutic Interventions. Circulation
117: 3238-3249
[Full Text]
Mallewa, J. E., Wilkins, E., Vilar, J., Mallewa, M., Doran, D., Back, D., Pirmohamed, M.
(2008). HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother
0: dkn251v1-13
[Abstract][Full Text]
Roth, J. D., Roland, B. L., Cole, R. L., Trevaskis, J. L., Weyer, C., Koda, J. E., Anderson, C. M., Parkes, D. G., Baron, A. D.
(2008). Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA
105: 7257-7262
[Abstract][Full Text]
Ahima, R. S., Lazar, M. A.
(2008). Adipokines and the Peripheral and Neural Control of Energy Balance. Mol. Endocrinol.
22: 1023-1031
[Abstract][Full Text]
Chehab, F. F.
(2008). Minireview: Obesity and LipOdystrophy--Where Do the Circles Intersect?. Endocrinology
149: 925-934
[Abstract][Full Text]
Park, J. Y., Chong, A. Y., Cochran, E. K., Kleiner, D. E., Haller, M. J., Schatz, D. A., Gorden, P.
(2008). Type 1 Diabetes Associated with Acquired Generalized Lipodystrophy and Insulin Resistance: The Effect of Long-Term Leptin Therapy. J. Clin. Endocrinol. Metab.
93: 26-31
[Abstract][Full Text]
Kosmiski, L. A, Bessesen, D. H, Stotz, S. A, Koeppe, J. R, Horton, T. J
(2007). Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy. Am. J. Clin. Nutr.
86: 1009-1015
[Abstract][Full Text]
Bermudez-Humaran, L. G., Nouaille, S., Zilberfarb, V., Corthier, G., Gruss, A., Langella, P., Issad, T.
(2007). Effects of Intranasal Administration of a Leptin-Secreting Lactococcus lactis Recombinant on Food Intake, Body Weight, and Immune Response of Mice. Appl. Environ. Microbiol.
73: 5300-5307
[Abstract][Full Text]
Beltrand, J., Beregszaszi, M., Chevenne, D., Sebag, G., De Kerdanet, M., Huet, F., Polak, M., Tubiana-Rufi, N., Lacombe, D., De Paoli, A. M., Levy-Marchal, C.
(2007). Metabolic Correction Induced by Leptin Replacement Treatment in Young Children With Berardinelli-Seip Congenital Lipoatrophy. Pediatrics
120: e291-e296
[Abstract][Full Text]
Bray, G. A., Greenway, F. L.
(2007). Pharmacological Treatment of the Overweight Patient. Pharmacol. Rev.
59: 151-184
[Full Text]
Huang, W., Dedousis, N., O'Doherty, R. M.
(2007). Hepatic steatosis and plasma dyslipidemia induced by a high-sucrose diet are corrected by an acute leptin infusion. J. Appl. Physiol.
102: 2260-2265
[Abstract][Full Text]
Chan, J. L., Wong, S. L., Orlova, C., Raciti, P., Mantzoros, C. S.
(2007). Pharmacokinetics of Recombinant Methionyl Human Leptin after Subcutaneous Administration: Variation of Concentration-Dependent Parameters According to Assay. J. Clin. Endocrinol. Metab.
92: 2307-2311
[Abstract][Full Text]
Beckman, J. A., Goldfine, A. B., Dunaif, A., Gerhard-Herman, M., Creager, M. A.
(2007). Endothelial Function Varies According to Insulin Resistance Disease Type. Diabetes Care
30: 1226-1232
[Abstract][Full Text]
Savage, D. B., Petersen, K. F., Shulman, G. I.
(2007). Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance. Physiol. Rev.
87: 507-520
[Abstract][Full Text]
Sutinen, J., Yki-Jarvinen, H.
(2007). Increased resting energy expenditure, fat oxidation, and food intake in patients with highly active antiretroviral therapy-associated lipodystrophy. Am. J. Physiol. Endocrinol. Metab.
292: E687-E692
[Abstract][Full Text]
Ebihara, K., Kusakabe, T., Hirata, M., Masuzaki, H., Miyanaga, F., Kobayashi, N., Tanaka, T., Chusho, H., Miyazawa, T., Hayashi, T., Hosoda, K., Ogawa, Y., DePaoli, A. M., Fukushima, M., Nakao, K.
(2007). Efficacy and Safety of Leptin-Replacement Therapy and Possible Mechanisms of Leptin Actions in Patients with Generalized Lipodystrophy. J. Clin. Endocrinol. Metab.
92: 532-541
[Abstract][Full Text]
Gao, J., Katagiri, H., Ishigaki, Y., Yamada, T., Ogihara, T., Imai, J., Uno, K., Hasegawa, Y., Kanzaki, M., Yamamoto, T. T., Ishibashi, S., Oka, Y.
(2007). Involvement of Apolipoprotein E in Excess Fat Accumulation and Insulin Resistance. Diabetes
56: 24-33
[Abstract][Full Text]
Foster-Schubert, K. E., Cummings, D. E.
(2006). Emerging Therapeutic Strategies for Obesity. Endocr. Rev.
27: 779-793
[Abstract][Full Text]
Ahima, R. S., Qi, Y., Singhal, N. S., Jackson, M. B., Scherer, P. E.
(2006). Brain Adipocytokine Action and Metabolic Regulation. Diabetes
55: S145-S154
[Abstract][Full Text]
da Silva, A. A., Tallam, L. S., Liu, J., Hall, J. E.
(2006). Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. Am. J. Physiol. Regul. Integr. Comp. Physiol.
291: R1275-R1282
[Abstract][Full Text]
Yao-Borengasser, A., Rasouli, N., Varma, V., Miles, L. M., Phanavanh, B., Starks, T. N., Phan, J., Spencer, H. J. III, McGehee, R. E. Jr., Reue, K., Kern, P. A.
(2006). Lipin Expression Is Attenuated in Adipose Tissue of Insulin-Resistant Human Subjects and Increases With Peroxisome Proliferator-Activated Receptor {gamma} Activation.. Diabetes
55: 2811-2818
[Abstract][Full Text]
Semple, R. K., Soos, M. A., Luan, J., Mitchell, C. S., Wilson, J. C., Gurnell, M., Cochran, E. K., Gorden, P., Chatterjee, V. K. K., Wareham, N. J., O'Rahilly, S.
(2006). Elevated Plasma Adiponectin in Humans with Genetically Defective Insulin Receptors. J. Clin. Endocrinol. Metab.
91: 3219-3223
[Abstract][Full Text]
Lee, J. H., Chan, J. L., Sourlas, E., Raptopoulos, V., Mantzoros, C. S.
(2006). Recombinant Methionyl Human Leptin Therapy in Replacement Doses Improves Insulin Resistance and Metabolic Profile in Patients with Lipoatrophy and Metabolic Syndrome Induced by the Highly Active Antiretroviral Therapy. J. Clin. Endocrinol. Metab.
91: 2605-2611
[Abstract][Full Text]
Utzschneider, K. M., Trence, D. L.
(2006). Effectiveness of Gastric Bypass Surgery in a Patient With Familial Partial Lipodystrophy.. Diabetes Care
29: 1380-1382
[Full Text]
Poirier, H., Shapiro, J. S., Kim, R. J., Lazar, M. A.
(2006). Nutritional Supplementation With trans-10, cis-12-Conjugated Linoleic Acid Induces Inflammation of White Adipose Tissue. Diabetes
55: 1634-1641
[Abstract][Full Text]
Gale, S. E., Frolov, A., Han, X., Bickel, P. E., Cao, L., Bowcock, A., Schaffer, J. E., Ory, D. S.
(2006). A Regulatory Role for 1-Acylglycerol-3-phosphate-O-acyltransferase 2 in Adipocyte Differentiation. J. Biol. Chem.
281: 11082-11089
[Abstract][Full Text]
Desvergne, B., Michalik, L., Wahli, W.
(2006). Transcriptional Regulation of Metabolism. Physiol. Rev.
86: 465-514
[Abstract][Full Text]
Durham, H. A., Truett, G. E.
(2006). Development of insulin resistance and hyperphagia in Zucker fatty rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.
290: R652-R658
[Abstract][Full Text]
Greenberg, A. S, Obin, M. S
(2006). Obesity and the role of adipose tissue in inflammation and metabolism. Am. J. Clin. Nutr.
83: 461S-465S
[Abstract][Full Text]
Oral, E. A., Javor, E. D., Ding, L., Uzel, G., Cochran, E. K., Young, J. R., DePaoli, A. M., Holland, S. M., Gorden, P.
(2006). Leptin Replacement Therapy Modulates Circulating Lymphocyte Subsets and Cytokine Responsiveness in Severe Lipodystrophy. J. Clin. Endocrinol. Metab.
91: 621-628
[Abstract][Full Text]
Lofgren, P., Andersson, I., Adolfsson, B., Leijonhufvud, B.-M., Hertel, K., Hoffstedt, J., Arner, P.
(2005). Long-Term Prospective and Controlled Studies Demonstrate Adipose Tissue Hypercellularity and Relative Leptin Deficiency in the Postobese State. J. Clin. Endocrinol. Metab.
90: 6207-6213
[Abstract][Full Text]
Toyoshima, Y., Gavrilova, O., Yakar, S., Jou, W., Pack, S., Asghar, Z., Wheeler, M. B., LeRoith, D.
(2005). Leptin Improves Insulin Resistance and Hyperglycemia in a Mouse Model of Type 2 Diabetes. Endocrinology
146: 4024-4035
[Abstract][Full Text]
Hegele, R. A., Pollex, R. L.
(2005). Genetic and physiological insights into the metabolic syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol.
289: R663-R669
[Abstract][Full Text]
Tanaka, T., Hidaka, S., Masuzaki, H., Yasue, S., Minokoshi, Y., Ebihara, K., Chusho, H., Ogawa, Y., Toyoda, T., Sato, K., Miyanaga, F., Fujimoto, M., Tomita, T., Kusakabe, T., Kobayashi, N., Tanioka, H., Hayashi, T., Hosoda, K., Yoshimatsu, H., Sakata, T., Nakao, K.
(2005). Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation Parallels Metabolic Phenotype in Leptin Transgenic Mice Under Dietary Modification. Diabetes
54: 2365-2374
[Abstract][Full Text]
Klebanov, S., Astle, C. M, DeSimone, O., Ablamunits, V., Harrison, D. E
(2005). Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility. J Endocrinol
186: 203-211
[Abstract][Full Text]
Milinkovic, A., Martinez, E.
(2005). Current perspectives on HIV-associated lipodystrophy syndrome. J Antimicrob Chemother
56: 6-9
[Abstract][Full Text]
Javor, E. D., Cochran, E. K., Musso, C., Young, J. R., DePaoli, A. M., Gorden, P.
(2005). Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy. Diabetes
54: 1994-2002
[Abstract][Full Text]
Unger, R. H.
(2005). Hyperleptinemia: Protecting the Heart From Lipid Overload. Hypertension
45: 1031-1034
[Abstract][Full Text]
Yu, Y.-H., Ginsberg, H. N.
(2005). Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin-Resistant Adipose Tissue. Circ. Res.
96: 1042-1052
[Abstract][Full Text]
Cochran, E., Musso, C., Gorden, P.
(2005). The Use of U-500 in Patients With Extreme Insulin Resistance. Diabetes Care
28: 1240-1244
[Full Text]
Shea, S. A., Hilton, M. F., Orlova, C., Ayers, R. T., Mantzoros, C. S.
(2005). Independent Circadian and Sleep/Wake Regulation of Adipokines and Glucose in Humans. J. Clin. Endocrinol. Metab.
90: 2537-2544
[Abstract][Full Text]
Sennello, J. A., Fayad, R., Morris, A. M., Eckel, R. H., Asilmaz, E., Montez, J., Friedman, J. M., Dinarello, C. A., Fantuzzi, G.
(2005). Regulation of T Cell-Mediated Hepatic Inflammation by Adiponectin and Leptin. Endocrinology
146: 2157-2164
[Abstract][Full Text]
Rasouli, N., Raue, U., Miles, L. M., Lu, T., Di Gregorio, G. B., Elbein, S. C., Kern, P. A.
(2005). Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am. J. Physiol. Endocrinol. Metab.
288: E930-E934
[Abstract][Full Text]
Savage, D. B., Petersen, K. F., Shulman, G. I.
(2005). Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation. Hypertension
45: 828-833
[Abstract][Full Text]
Goodpaster, B. H., Krishnaswami, S., Harris, T. B., Katsiaras, A., Kritchevsky, S. B., Simonsick, E. M., Nevitt, M., Holvoet, P., Newman, A. B.
(2005). Obesity, Regional Body Fat Distribution, and the Metabolic Syndrome in Older Men and Women. Arch Intern Med
165: 777-783
[Abstract][Full Text]
Svensson, J., Herlitz, H., Lundberg, P.-A., Johannsson, G.
(2005). Adiponectin, Leptin, and Erythrocyte Sodium/Lithium Countertransport Activity, But Not Resistin, Are Related to Glucose Metabolism in Growth Hormone-Deficient Adults. J. Clin. Endocrinol. Metab.
90: 2290-2296
[Abstract][Full Text]
Chan, J. L., Bullen, J., Stoyneva, V., DePaoli, A. M., Addy, C., Mantzoros, C. S.
(2005). Recombinant Methionyl Human Leptin Administration to Achieve High Physiologic or Pharmacologic Leptin Levels Does Not Alter Circulating Inflammatory Marker Levels in Humans with Leptin Sufficiency or Excess. J. Clin. Endocrinol. Metab.
90: 1618-1624
[Abstract][Full Text]
Savage, D. B., Murgatroyd, P. R., Chatterjee, V. K., O'Rahilly, S.
(2005). Energy Expenditure and Adaptive Responses to an Acute Hypercaloric Fat Load in Humans with Lipodystrophy. J. Clin. Endocrinol. Metab.
90: 1446-1452
[Abstract][Full Text]
Lazar, M. A.
(2005). How Obesity Causes Diabetes: Not a Tall Tale. Science
307: 373-375
[Abstract][Full Text]
Schwartz, M. W., Porte, D. Jr.
(2005). Diabetes, Obesity, and the Brain. Science
307: 375-379
[Abstract][Full Text]
Lee, Y., Naseem, R. H., Duplomb, L., Park, B.-H., Garry, D. J., Richardson, J. A., Schaffer, J. E., Unger, R. H.
(2004). Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. Proc. Natl. Acad. Sci. USA
101: 13624-13629
[Abstract][Full Text]
Ahima, R., Osei, S. Y.
(2004). Leptin and Appetite Control in Lipodystrophy. J. Clin. Endocrinol. Metab.
89: 4254-4257
[Full Text]
McDuffie, J. R., Riggs, P. A., Calis, K. A., Freedman, R. J., Oral, E. A., DePaoli, A. M., Yanovski, J. A.
(2004). Effects of Exogenous Leptin on Satiety and Satiation in Patients with Lipodystrophy and Leptin Insufficiency. J. Clin. Endocrinol. Metab.
89: 4258-4263
[Abstract][Full Text]
Steinberg, G. R., Smith, A. C., van Denderen, B. J. W., Chen, Z., Murthy, S., Campbell, D. J., Heigenhauser, G. J. F., Dyck, D. J., Kemp, B. E.
(2004). AMP-Activated Protein Kinase Is Not Down-Regulated in Human Skeletal Muscle of Obese Females. J. Clin. Endocrinol. Metab.
89: 4575-4580
[Abstract][Full Text]
Cohen, P., Friedman, J. M.
(2004). Leptin and the Control of Metabolism: Role for Stearoyl-CoA Desaturase-1 (SCD-1). J. Nutr.
134: 2455S-2463S
[Abstract][Full Text]
Meier, U., Gressner, A. M.
(2004). Endocrine Regulation of Energy Metabolism: Review of Pathobiochemical and Clinical Chemical Aspects of Leptin, Ghrelin, Adiponectin, and Resistin. Clin. Chem.
50: 1511-1525
[Abstract][Full Text]
Ebihara, K., Masuzaki, H., Nakao, K.
(2004). Long-Term Leptin-Replacement Therapy for Lipoatrophic Diabetes. NEJM
351: 615-616
[Full Text]
Javor, E. D., Moran, S. A., Young, J. R., Cochran, E. K., DePaoli, A. M., Oral, E. A., Turman, M. A., Blackett, P. R., Savage, D. B., O'Rahilly, S., Balow, J. E., Gorden, P.
(2004). Proteinuric Nephropathy in Acquired and Congenital Generalized Lipodystrophy: Baseline Characteristics and Course during Recombinant Leptin Therapy. J. Clin. Endocrinol. Metab.
89: 3199-3207
[Abstract][Full Text]
Koutkia, P., Canavan, B., Breu, J., Johnson, M. L, Depaoli, A., Grinspoon, S. K
(2004). Relation of leptin pulse dynamics to fat distribution in HIV-infected patients. Am. J. Clin. Nutr.
79: 1103-1109
[Abstract][Full Text]
Wong, S. L., DePaoli, A. M., Lee, J. H., Mantzoros, C. S.
(2004). Leptin Hormonal Kinetics in the Fed State: Effects of Adiposity, Age, and Gender on Endogenous Leptin Production and Clearance Rates. J. Clin. Endocrinol. Metab.
89: 2672-2677
[Abstract][Full Text]
Banks, W. A., Coon, A. B., Robinson, S. M., Moinuddin, A., Shultz, J. M., Nakaoke, R., Morley, J. E.
(2004). Triglycerides Induce Leptin Resistance at the Blood-Brain Barrier. Diabetes
53: 1253-1260
[Abstract][Full Text]
Cochran, E., Young, J. R., Sebring, N., DePaoli, A., Oral, E. A., Gorden, P.
(2004). Efficacy of Recombinant Methionyl Human Leptin Therapy for the Extreme Insulin Resistance of the Rabson-Mendenhall Syndrome. J. Clin. Endocrinol. Metab.
89: 1548-1554
[Abstract][Full Text]
Popovic, V., Djurovic, M., Cetkovic, A., Vojvodic, D., Pekic, S., Spremovic, S., Petakov, M., Damjanovic, S., Milic, N., Dieguez, C., Casanueva, F. F.
(2004). Inhibin B: A Potential Marker of Gonadal Activity in Patients with Anorexia Nervosa during Weight Recovery. J. Clin. Endocrinol. Metab.
89: 1838-1843
[Abstract][Full Text]
Haluzik, M., Gavrilova, O., LeRoith, D.
(2004). Peroxisome Proliferator-Activated Receptor-{alpha} Deficiency Does Not Alter Insulin Sensitivity in Mice Maintained on Regular or High-Fat Diet: Hyperinsulinemic-Euglycemic Clamp Studies. Endocrinology
145: 1662-1667
[Abstract][Full Text]
Licinio, J., Caglayan, S., Ozata, M., Yildiz, B. O., de Miranda, P. B., O'Kirwan, F., Whitby, R., Liang, L., Cohen, P., Bhasin, S., Krauss, R. M., Veldhuis, J. D., Wagner, A. J., DePaoli, A. M., McCann, S. M., Wong, M.-L.
(2004). Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc. Natl. Acad. Sci. USA
101: 4531-4536
[Abstract][Full Text]
Garg, A.
(2004). Acquired and Inherited Lipodystrophies. NEJM
350: 1220-1234
[Full Text]
Benavides, S., Nahata, M. C
(2004). Pharmacologic Therapy for HIV-Associated Lipodystrophy. The Annals of Pharmacotherapy
38: 448-457
[Abstract][Full Text]
Bays, H., Mandarino, L., DeFronzo, R. A.
(2004). Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach. J. Clin. Endocrinol. Metab.
89: 463-478
[Full Text]
Snijder, M. B., Dekker, J. M., Visser, M., Bouter, L. M., Stehouwer, C. D.A., Yudkin, J. S., Heine, R. J., Nijpels, G., Seidell, J. C.
(2004). Trunk Fat and Leg Fat Have Independent and Opposite Associations With Fasting and Postload Glucose Levels: The Hoorn Study. Diabetes Care
27: 372-377
[Abstract][Full Text]
Havel, P. J.
(2004). Update on Adipocyte Hormones: Regulation of Energy Balance and Carbohydrate/Lipid Metabolism. Diabetes
53: S143-151
[Abstract][Full Text]
Steinberg, G. R., Smith, A. C., Wormald, S., Malenfant, P., Collier, C., Dyck, D. J.
(2004). Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle. Am. J. Physiol. Endocrinol. Metab.
286: E57-E63
[Abstract][Full Text]
Gavrila, A., Chan, J. L., Yiannakouris, N., Kontogianni, M., Miller, L. C., Orlova, C., Mantzoros, C. S.
(2003). Serum Adiponectin Levels Are Inversely Associated with Overall and Central Fat Distribution but Are Not Directly Regulated by Acute Fasting or Leptin Administration in Humans: Cross-Sectional and Interventional Studies. J. Clin. Endocrinol. Metab.
88: 4823-4831
[Abstract][Full Text]
Rajala, M. W., Scherer, P. E.
(2003). Minireview: The Adipocyte--At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis. Endocrinology
144: 3765-3773
[Abstract][Full Text]
Couturier, C., Jockers, R.
(2003). Activation of the Leptin Receptor by a Ligand-induced Conformational Change of Constitutive Receptor Dimers. J. Biol. Chem.
278: 26604-26611
[Abstract][Full Text]
Owen, K. R., Stride, A., Ellard, S., Hattersley, A. T.
(2003). Etiological Investigation of Diabetes in Young Adults Presenting With Apparent Type 2 Diabetes. Diabetes Care
26: 2088-2093
[Abstract][Full Text]
Bloomgarden, Z. T.
(2003). Fat Metabolism and Diabetes: 2003 American Diabetes Association Postgraduate Course. Diabetes Care
26: 2198-2203
[Full Text]
Iwaki, M., Matsuda, M., Maeda, N., Funahashi, T., Matsuzawa, Y., Makishima, M., Shimomura, I.
(2003). Induction of Adiponectin, a Fat-Derived Antidiabetic and Antiatherogenic Factor, by Nuclear Receptors. Diabetes
52: 1655-1663
[Abstract][Full Text]
Gavrila, A., Peng, C.-K., Chan, J. L., Mietus, J. E., Goldberger, A. L., Mantzoros, C. S.
(2003). Diurnal and Ultradian Dynamics of Serum Adiponectin in Healthy Men: Comparison with Leptin, Circulating Soluble Leptin Receptor, and Cortisol Patterns. J. Clin. Endocrinol. Metab.
88: 2838-2843
[Abstract][Full Text]
Lyon, C. J., Law, R. E., Hsueh, W. A.
(2003). Minireview: Adiposity, Inflammation, and Atherogenesis. Endocrinology
144: 2195-2200
[Abstract][Full Text]
Leow, M. K. S., Addy, C. L., Mantzoros, C. S.
(2003). Human Immunodeficiency Virus/Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome: Clinical Presentation, Pathophysiology, and Therapeutic Strategies. J. Clin. Endocrinol. Metab.
88: 1961-1976
[Full Text]
Sivitz, W. I., Wayson, S. M., Bayless, M. L., Larson, L. F., Sinkey, C., Bar, R. S., Haynes, W. G.
(2003). Leptin and Body Fat in Type 2 Diabetes and Monodrug Therapy. J. Clin. Endocrinol. Metab.
88: 1543-1553
[Abstract][Full Text]
Munoz, J., Gower, B. A.
(2003). Relationship between Serum Leptin Concentration and Low-Density Muscle in Postmenopausal Women. J. Clin. Endocrinol. Metab.
88: 1157-1161
[Abstract][Full Text]
Guldstrand, M., Ahren, B., Adamson, U.
(2003). Improved beta -cell function after standardized weight reduction in severely obese subjects. Am. J. Physiol. Endocrinol. Metab.
284: E557-E565
[Abstract][Full Text]
Halle, M., Persson, P. B.
(2003). Role of leptin and leptin receptor in inflammation. Am. J. Physiol. Regul. Integr. Comp. Physiol.
284: R760-R762
[Full Text]
Addy, C. L., Gavrila, A., Tsiodras, S., Brodovicz, K., Karchmer, A. W., Mantzoros, C. S.
(2003). Hypoadiponectinemia Is Associated with Insulin Resistance, Hypertriglyceridemia, and Fat Redistribution in Human Immunodeficiency Virus-Infected Patients Treated with Highly Active Antiretroviral Therapy. J. Clin. Endocrinol. Metab.
88: 627-636
[Abstract][Full Text]
Colombo, C., Haluzik, M., Cutson, J. J., Dietz, K. R., Marcus-Samuels, B., Vinson, C., Gavrilova, O., Reitman, M. L.
(2003). Opposite Effects of Background Genotype on Muscle and Liver Insulin Sensitivity of Lipoatrophic Mice. ROLE OF TRIGLYCERIDE CLEARANCE. J. Biol. Chem.
278: 3992-3999
[Abstract][Full Text]
Freemark, M.
(2003). Pharmacologic Approaches to the Prevention of Type 2 Diabetes in High Risk Pediatric Patients. J. Clin. Endocrinol. Metab.
88: 3-13
[Full Text]
Simha, V., Szczepaniak, L. S., Wagner, A. J., DePaoli, A. M., Garg, A.
(2003). Effect of Leptin Replacement on Intrahepatic and Intramyocellular Lipid Content in Patients With Generalized Lipodystrophy. Diabetes Care
26: 30-35
[Abstract][Full Text]
Laustsen, P. G., Michael, M. D., Crute, B. E., Cohen, S. E., Ueki, K., Kulkarni, R. N., Keller, S. R., Lienhard, G. E., Kahn, C. R.
(2002). Lipoatrophic diabetes in Irs1-/-/Irs3-/- double knockout mice. Genes Dev.
16: 3213-3222
[Abstract][Full Text]
Simha, V., Zerwekh, J. E., Sakhaee, K., Garg, A.
(2002). Effect of Subcutaneous Leptin Replacement Therapy on Bone Metabolism in Patients with Generalized Lipodystrophy. J. Clin. Endocrinol. Metab.
87: 4942-4945
[Abstract][Full Text]
Colombo, C., Cutson, J. J., Yamauchi, T., Vinson, C., Kadowaki, T., Gavrilova, O., Reitman, M. L.
(2002). Transplantation of Adipose Tissue Lacking Leptin Is Unable to Reverse the Metabolic Abnormalities Associated With Lipoatrophy. Diabetes
51: 2727-2733
[Abstract][Full Text]
Garg, A., Misra, A.
(2002). Hepatic Steatosis, Insulin Resistance, and Adipose Tissue Disorders. J. Clin. Endocrinol. Metab.
87: 3019-3022
[Full Text]
Grunfeld, C.
(2002). Leptin and the Immunosuppression of Malnutrition. J. Clin. Endocrinol. Metab.
87: 3038-3039
[Full Text]
Oral, E. A., Ruiz, E., Andewelt, A., Sebring, N., Wagner, A. J., Depaoli, A. M., Gorden, P.
(2002). Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy. J. Clin. Endocrinol. Metab.
87: 3110-3117
[Abstract][Full Text]
Chou, C. J., Haluzik, M., Gregory, C., Dietz, K. R., Vinson, C., Gavrilova, O., Reitman, M. L.
(2002). WY14,643, a Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Agonist, Improves Hepatic and Muscle Steatosis and Reverses Insulin Resistance in Lipoatrophic A-ZIP/F-1 Mice. J. Biol. Chem.
277: 24484-24489
[Abstract][Full Text]
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