Obesity & Lipodystrophy - Medical College of Wisconsin

Lipodystrophies 

Sixth Annual Diabetes Symposium of Wisconsin 

May 17, 2013 

Abhimanyu Garg, M.D. 

Professor of Internal Medicine 

Chief, Division of Nutrition and Metabolic Diseases 

Distinguished Chair in Human Nutrition Research 

UT Southwestern Medical Center

Disclosures 

Research support/ Speaker/ Consultant/Advisory Board 

For 

Amylin/ Bristol-Myers Squibb 

Merck 

Pfizer 

Aegerion


Disorders characterized by 

selective loss of adipose tissue. 

• Genetic 

• Acquired

Metabolic Complications of 


• Insulin resistance, Premature DM 

• Hypertriglyceridemia, low HDL cholesterol 

• Polycystic ovarian syndrome 

• Acanthosis nigricans 

• Hepatic Steatosis 

• Hypertension (rare)

Acquired Lipodystrophies 

Generalized Partial HAART-induced 

(HIV-Patient) 

Localized

Genetic Lipodystrophies 

Autosomal Recessive 

• Congenital generalized 

lipodystrophy (CGL) 

• Mandibuloacral dysplasia 

(MAD)-associated 

• Autoinflammatory (JMP) 

• Other types 

– FPL 

– SHORT syndrome 

– Neonatal Progeroid 

syndrome 

– MDP syndrome 

Autosomal Dominant 

• Familial partial lipodystrophy 

(FPL) 

• Atypical progeroid 

syndrome 

• Hutchinson-Gilford progeria 

syndrome 

• SHORT syndrome

Congenital Generalized Lipodystrophy 

(Berardinelli-Seip Syndrome) 

• Autosomal recessive 

• Prevalence < 1 in 10 million 

• Reported in ~300 patients of 

various ethnicities

CGL Phenotype

Serum Leptin Levels in CGL 

5 

4 

~7 th %ile for M 

F 

Median 

Leptin (ng/mL) 

3 

2 

1 

0 

M F 

CGL1 

(APGAT2) (AGPAT2) 

M F 

CGL2 

(SEIPIN) 

Haque et al. JCEM 87:2395-8, 2002

Linkage of CGL1 locus to 9q34 

CG100 

CG300 

CG400 

CG600 

CG700 

D9S934 

LOD Score 

-4.0 

0.0 

-2.0 0.0 2.0 4.0 6.0 

1 2 3 

4 5 

1 2 

3 4 5 6 7 8 9 

1 2 3 

4 5 6 

1 2 

3 4 5 6 7 

D9S1825 

8.5 

HLOD17 

LOD15 

CG800 

CG900 

CG1000 

CG1100 

CG1300 

CG2800 

1 2 

3 4 

1 2 3 

4 6 7 8 9 

1 2 

3 4 5 6 7 8 

CG3100 

3 6 

9 10 11 

1 2 

3 

1 2 

3 4 5 

1 2 

3 4 

D9S915 

D9S2157 

D9S164 

D9S1793 

D9S1818 

17.2 

18.9 

19.9 

22.9 

21 22 23 24 

CG3300 

CG2900 

1 2 

CG3000 

1 2 

1 2 

CG3200 

1 2 

1 2 5 

3 4 

CG3500 

1 2 

D9S1826 

D9S158 

D9S1838 

D9S905 

31.6 

33.7 

35.9 

3 4 5 6 7 

3 4 

3 4 5 6 

3 4 

3 4 5 6 

D9S2168 41.0 

qTEL 

Garg et al. JCEM 84; 3390-4, 1999

D9S1818 

AGS3 

CARD9 

D9S1826 

SNAPC4 

PP15PIV 

LHX3 

D9S158 

NOTCH1 

AGPAT2 

EDF1 

D9S905 

DPP7 

PTGDS 

DPP7 

D9S1838 

Physical Map of 9q34 Region 

AGPAT2 Mutations in CGL, Type 1 

cen---- 

TR 

TF 

(BAC 2521H7) 

---qtel 

L228P 

A239V 

G136R 

F140del L126fsX146 

V167fsX183 R68X 

3’ 

5’ 

6 

5 

4 

3 

2 

1 

916C>G 

-2A>C 

-2A>G 

Ex3-4del 

• Agarwal et al. Nat Genet 31: 21-23; 2002

AGPAT2 mutations in CGL, type 1 

(TG biosynthetic pathway) 

2-Monoacylglycerol 

H 2 

C 

HC 

OH 

OH 

GPAT 

H 2 

C 

HC 

O 

OH 

O 

C 

R 1 

AGPAT2 

mutated 

in CGL1 

AGPAT 

H 2 

C 

HC 

O 

O 

O 

C 

O 

C 

R 1 

R 2 

PP 

Acyl-CoA 

CoA 

H 2 

C 

HC 

O 

O 

MGAT 

O 

C 

O 

C 

R 1 

R 2 

DGAT 

H 2 

C 

HC 

O 

O 

O 

C 

O 

C 

O 

R 1 

R 2 

H 2 

C 

OPO 3 

2- 

Glycerol- 

3-Phosphate 

Acyl- 

CoA 

CoA 

H 2 

C 

OPO 3 

2- 

1-Acylglycerol- 

3-Phosphate 

(Lysophosphatidic Acid) 

Acyl- 

CoA 

CoA 

H 2 

C 

OPO 3 

2 - 

1,2 Diacylglycerol 

Phosphate 

(Phosphatidic Acid) 

H 2 

C 

O H 

H 2 O P i Acyl - 

CoA 

CoA 

H 2 

C 

1,2 Diacylglycerol Triacylglycerol 

O 

C 

R 3 

Phosphatidyl Inositol 

Cardiolipin 

Phosphatidyl Choline 

Phosphatidyl Ethanolamine 

Phosphatidyl Serine

mRNA Expression of AGPAT 

Isoforms in Human Tissues 

adipose tissue liver muscle 

- G3PDH 

]- AGPATs 

AGPAT 

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 

• Agarwal et al. Nat Genet 31: 21-23; 2002

MRI of Agpat2 -/- Mice 

Male 

Female 

WT Agpat2 -/- WT Agpat2 -/- 

Cortés et al. Cell Metab 9:165-176, 2009

Increased Lipid Staining in Livers of 

Male Agpat2 -/- Mice 

Wild-type Agpat2 -/- 

A 

B 

H&E 

C 

D 

Oil Red O 


Wild Type 

Agpat2 -/- 

GLYCEROL- 3 - PHOSPHATE 

GLYCEROL- 3 - PHOSPHATE 

Fatty acid-CoA 

CoA 

GPATs 


CoA 

GPATs 

LYSOPHOSPHATIDIC 

ACID 

LYSOPHOSPHATIDIC 

ACID 


CoA 

AGPATs 

LPPs 


CoA 

AGPAT1,3-8 

AGPAT2 

PHOSPHATIDIC ACID 

PHOSPHATIDIC ACID 

2-MONOACYLGLYCEROL 

PAPs 

Fatty acid- 

CoA 

MGATs 

CoA 

DIACYLGLYCEROL 

2-MONOACYLGLYCEROL 

Fatty acid- 

CoA 

CoA 

MGATs 

PAPs 

DIACYLGLYCEROL 


CoA 

DGATs 


CoA 

DGATs 

Chylomicrons 

Chylomicrons 

TRIACYLGLYCEROL 

TRIACYLGLYCEROL 

Chylomicrons 

Remnant Receptor 

Chylomicrons 

Remnant Receptor 


Mechanism of Hepatic Insulin Resistance 

(Protein Expression) 


BSCL2 Mutations in CGL, Type 2 

• BSCL2 located on chromosome 11q13 

• Encodes a 462 amino acid transmembrane ER 

protein, seipin 

• Seipin has a CAAX motif at C-terminal and 

an N-glycosylation site 

• Role in lipid droplet formation and adipocyte 

differentiation 

• Magre et al. Nat Genet 2001;28:365-70 

• Windpassinger et al. Nat. Genet. 2004; 36:271-6 

• Agarwal & Garg. Trends Mol. Med. 2004;10:440-4 

Szymanski et al. PNAS 104:20890-20895, 2007 

Fei et al. J Cell Biol 180:473-482, 2008 

Payne et al. Diabetes 57:2055-2060, 2008

Lipid Droplet Formation and Seipin 

Nuclear pore 

Lipid droplet 

Glycerol-3-P 

FA-CoA 

GPATs 

CoA 

Nuclear pore 

Nucleus 

FA-CoA 

CoA 

LPA 

AGPATs 

Nucleus 

PA 

Pi 

PAPs 

ER 

FA-CoA 

CoA 

DAG 

TG 

DGATs 

ER 

Lipid droplet 

fusion 

Normal 

Seipin Deficiency 

Garg and Agarwal. BBA: 1791:507-13. 2009

Phenotypic Differences in CGL Patients 

Mental Retardation 

Cardiomyopathy 

Lytic bone lesions 

Loss of Mechanical Fat 

Metabolic Abnormalities 

CGL1 

(AGPAT2) 

– 

– 

++ 

– 

+++ 

CGL2 

(BSCL2) 

+ 

+ 

– 

++ 

+++ 

• Magre´ J, et al. Nat Genet 2001;28:365-70 

• Agarwal, Simha et al. JCEM 2003; 88:4840-47 

• van Meldergem et al. J Hum Genet 2003;39:722-33

CGL1 

(AGPAT2) 

CGL2 

(BSCL2) 

C 

Normal 

• Simha & Garg. JCEM 88: 5433-7, 2003

CGL1 

(AGPAT2) 

CGL2 

(BSCL2) 

Normal 

• Simha & Garg. JCEM 88: 5433-7, 2003

CGL1 

(AGPAT2) 

CGL2 

(BSCL2) 

C 

Normal 

• Simha & Garg. JCEM 88: 5433-7, 2003

Caveolin 1 mutation in CGL, Type 3 

Caveolae 

Nuclear pore 

PTRF/Cavin Caveolin-1 

Nucleus 

Caveolin 

vesicle 

Perilipin 

ER 

Lipid droplet 

CIDEC 

8.8 y 20 y 

Kim, CA et al. JCEM 2008;93:1129-1134 

Garg and Agarwal, JCEM 2008;93:1183-1185

Novel CGL, type 4 

CG7100 

• Two affected siblings 

• Congenital myopathy 

• Muscle Bx: Non-specific 

• Elevated CK levels 

• Atlantoaxial instability 

Simha et al. Am J Med Genet.146A:2318-26, 2008.

Polymerase I and transcript release factor (PTRF) mutations in CGL4 

PTRF/Cavin 

Hayashi et al. J Clin Invest 119: 2623-33; 2009.

Amplitude (µV) 

50µV 

CGL, Type 4 

A 

(Additional Phenotypic Features) 

A. 

• Percussion induced muscle mounding D 

• Congenital pyloric stenosis 

• Long QT interval 

B. 

• Predisposition to arrhythmias/sudden death 

• Catecholaminergic polymorphic ventricular 

C. 

tachycardia 

30ms 

Time (ms) 

Hayashi et al. J Clin Invest 119: 2623-33; 2009. 

Shastry et al. Am J Med Genet 2010;152A:2245-53. 

Rajab et al. Plos Genet 2010;6:e1000874.

Congenital Generalized Lipodystrophy 

(Our Experience) 

• 118 Pedigrees genotyped 

• AGPAT2 mutations: 67 

• BSCL2 mutations: 32 

• CAV1 mutation: 0 

• PTRF mutations: 3 

• Unexplained: 16

Familial Partial Lipodystrophy 

(Dunnigan type) 

• Autosomal dominant 

• Prevalence < 1 in 10 million 

• Described in ~ 300 patients 

mainly of European ancestry

Familial Partial Lipodystrophy, Dunnigan type 

Female 

Male

Haque et al. JCEM 87: 2395-2398, 2002 

Serum Leptin Levels in FPL, Dunnigan 

60 

Males 

Females 

55 

~7 th %ile for M 

F 

Leptin (ng/mL) 

10 

5 

0 

15 20 25 30 35 40 

BMI (kg/m 2 )

F200 

1 2 

FPLD Pedigrees 

F300 

F500 

1 2 3 

3 4 5 6 7 8 9 10 11 12 

1 2 

4 5 6 7 8 9 10 

3 4 5 6 7 8 

11 12 13 14 15 

13 14 15 16 17 18 19 20 21 22 23 24 25 

9 10 11 12 13 14 

16 17 18 19 20 21 22 

F600 

1 2 

26 27 28 

F700 

1 2 

23 24 25 26 

3 4 5 6 7 8 9 10 

3 4 5 6 7 8 9 10 11 

11 12 13 14 15 16 17 18 19 20 21 22 

12 13 14 15 16 17 18 19 20 21 22 23 

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 

23 24 25 26 27 28 29 30 31 32 33 34 

50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 

Peters et al. Nat Genet 18: 292-5, 1998

FPLD Locus on Chromosome 1q21-22 

Loci 

D1S1631 

cM 

0.0 

-6.0 

LOD Score 

-4.0 -2.0 0.0 2.0 4.0 6.0 8.0 

D1S534 

Cen 

D1S442 

D1S305 

D1S2721 

D1S2624 

D1S1600 

D1S1653 

D1S1167 

Apo AII 

D1S1679 

D1S1677 

15.6 

18.3 

22.4 

23.6 

25.6 

27.7 

29.2 

33.3 

34.8 

35.4 

39.3 

D1S518 

66.3 

Peters et al. Nat Genet 

18: 292-5, 1998

Lamin A/C Mutations in FPLD 

16kb 

2kb 

5' // // // 3' 

1 2 3 4 5 6 7 8 9 10 11 12 

R482Q 

* Cardiomyopathy 

† Emery-Dreifuss Muscular Dystrophy 

‡ Limb Girdle Muscular Dystrophy 

§ Mild Myopathy 

Mild Lipodystrophy 

Cao and Hegele. Hum Mol Genet 9:109-112, 2002 

Garg A. N Engl J Med 350; 1220-34, 2004

Structure of Nuclear Lamina 

• Garg A. N Engl J Med 2004:350; 1220-34.

Pathogenesis of lipodystrophy in FPLD 

patients 

• LMNA mutations induce nuclear 

dysfunction resulting in premature death 

or apoptosis of adipocytes 

• Why fat loss spares the face, neck and 

intra-abdominal region?


PPARG Mutation 

FPL Normal 

Arm 

Forearm 

Thigh 

Calf 

Agarwal & 

Garg. 

JCEM 2002; 

87: 408-11

PPARG Mutations in FPL 

Agarwal & Garg. JCEM 2002; 87: 408-11 

Hegele et al. Diabetes 2002;51:3586-90 

Savage et al. Diabetes 2003; 52:910-17 

Garg A. N Engl J Med 350; 1220-34, 2004

Phenotypic Differences in FPL Patients 

Peripheral Fat Loss 

Fat excess in Face/Neck 

Cardiomyopathy 

Hypertension 

Onset of Lipodystrophy 

FPLD2 

(LMNA) 

+++ 

+++ 

+ 

+/- 

Puberty 

FPLD3 

(PPARG) 

+/++ 

-/+ 

- 

++ 

Variable

FPL: AKT2 gene 

(v-akt murine thymoma viral oncogene homolog 2) 

PI-dependent Ser-Thr protein kinase 

• R274H heterozygous 

mutation in a pedigree with 

lipodystrophy, DM and 

insulin resistance 

Courtesy of Stephen O’Rahilly 

George S, et al. Science 304; 1325-28, 2004 

Agarwal & Garg. Ann Rev Genomics Human Genet 7: 175-199, 2006.

CIDEC mutation in autosomal 

recessive FPL 

Perilipin Staining 

Patient 

Control 

Vessels 

Rubio-Cabezas et al. EMBO Mol Med 1: 280-287, 2009

FPL, PLIN1 Mutations 

Gandotra et al. NEJM 364, 740-8; 2011




• LMNA mutations: 92 

• PPARG mutations: 5 

• PLIN1 mutation: 0 

• AKT2 mutations: 0 

• CIDEC mutation: 0 

• Unexplained: 144

Familial Partial Lipodystrophy, Other Type

Thigh 

Calf 

Heterogeneity in FPL phenotype (Whole body MRI) 

FPL (other type) 

FPL (Dunnigan) FPL (PPARG) 

Normal 

FPL (other type) 

FPL (Dunnigan) FPL (PPARG) 

Normal 

D

FPL 122

FPL 122 

F122 

1 

2 

4 5 6 7 

3 10 8 

9 

11 

12 

13 

15 

16 

14 

* Exome Sequencing

FPL 122 

• Exome sequencing 3 persons 

• Filters: 

• Linkage region 

• Functional variants 

• Not in 1000G and dbSNP 

• 5 variants left- 3 novel 

• One of them highly expressed in adipose 

tissue (Good candidate)


(Future Directions) 

• Detailed phenotyping of PPARG, AKT2, 

CIDEC and PLIN1 subtypes 

• Search for additional loci 

• Understanding role of lamin A/C in adipocyte 

survival 

• Understanding additional pathways involved in 

lipodystrophy-induced insulin resistance

MAD associated Lipodystrophy and Progeroid 

Syndrome 

(LMNA homozygous Arg527His mutation) 

• 20-year-old Hispanic 

female 

• Beaked nose, small 

mouth 

• Bird-like faces 

• Contractures of 5 th 

fingers 

• Skin atrophy and loss of 

SC fat from dorsum of 

hands 

SImha & Garg. JCEM 87; 776-85, 2002 

Simha et al. JCEM 88: 2821-2824, 2003

MAD associated Lipodystrophy and 

Progeroid Syndrome 

LMNA Hom R527C 

LMNA Hom R527H 

Patient 

Control 

Agarwal et al. JCEM 2008;93:4617-23.

MAD associated Lipodystrophy and 

Progeroid Syndrome 

(Compound heterozygous ZMPSTE24 mutations) 

Age 2 

Age 18 

• Skin atrophy and 

contractures - age 2 

• Pinched nose 

• Skin contractures around 

interphalangeal joints 

• Sparse, brittle, grey hair 

• Generalized lipodystrophy 

• Died at age 24 from focal 

segmental glomerulosclerosis 

(FSGS) 

•Agarwal et al. Hum Mol Genet 2003;12:1195-2001

Post-translational Modification of 

Lamin A 

Michaelis & Hrycyna. Science 2013; 339: 1529-30. 

WT 

FT 

Lamin 

Lamin A/C 

A 

C 

•Shackleton et al. J Med Genet 42: e36, 2005

MAD-associated Lipodystrophy 



• LMNA mutations: 16 

• ZMPSTE24 mutations: 5 

• Unexplained: 5

Mandibular Hypoplasia, Deafness and Progeroid 

(MDP) Syndrome 

Shastry et al. JCEM 2010;95:E192-7.

Mandibular Hypoplasia, Deafness and Progeroid 

(MDP) Syndrome 

Clinical Feature 

MAD (LMNA) 

n=28 

MAD (ZMPSTE24) 

n=8 

Mandibular hypoplasia + + + 

Sclerodermatous skin + + + 

MDP 

n=7 

Lipodystrophy Partial Partial Partial/generalized 

Clavicular hypoplasia + + - 

Acro-osteolysis + + - 

Deafness - - + 

Undescended testes, 

male hypogonadism 

- - + 

Shastry et al. JCEM 2010;95:E192-7.

Hutchinson-Gilford Progeria Syndrome 

(LMNA p.G608G Het Mutation) 

Progeria at 19, 2 and 7 years of age 

Photo provided by The Progeria Research Foundation 

www.progeriaresearch.org

Atypical Progeroid Syndrome 

(LMNA Heterozygous Mutations) 

P4R 

E159K D136H C588R P4R 

C588R

Joint Contractures, Microcytic Anemia, and Panniculitis-induced 

(JMP) Lipodystrophy 

Garg et al. JCEM 2010; 95:E58-63 

JMP100 

1 2 

3 

4 

JMP200 

1 2 

5 6 7 

8 3 4 

9

31.5 Mb 

B Allele Frequency 

0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 

32.0 Mb 

32.5 Mb 

33.0 Mb 

33.5 Mb 

JMP200.4 

JMP200.3 

JMP100.3 

34.0 Mb 

F.U. / μg protein 

Agarwal et al. AJHG 2010;87:866-72. 

20S 

PA700 

Control 

JMP200.4 

Figure 1 

A 

PSMB8 mutation in JMP syndrome 

Figure 2 

A 

B 

Gly119 

6.4 Å 

Human 69 MAHGTTTLAFKFQHGVI 

Chimpanzee 69 MAHGTTTLAFKFQHGVI 

Dog 69 MVHGTTTLAFKFQHGVI 

Cow 69 MAHGTTTLAFKFQHGVI 

Mouse 69 MAHGTTTLAFKFQHGVI 

Zebrafish 64 LNHGTTTLAFKFRHGVI 

Thr73 

Gly119 

7.6 Å 

Thr73 

Thr75 

Met75 

B 

Chr 6 25.0 30.0 35.0 40.0 Mb 

Tel 

5’ 

3’ 

3’ 5’ 

Cent 

PSMB8 (wild-type) 

Mutant PSMB8 (Thr75Met) 

C 

5’ 

3’ 

1A 1B 2 3 4 5 6 

3’ 5’ 

D Wild Type E het224C>T F 

3’ 

5’ 

hom224C>T 

C 

10000 

9000 

8000 

7000 

6000 

5000 

4000 

3000 

2000 

1000 

0 

p=0.02 

p=0.11 

Control 

JMP200.4 

p=0.21 

D 

Lymphoblast 

┌────────┐ 

Rpt2 

Rpn12 

2 

5i 

5 

A C C A C G C 

Thr 

74 

Thr 

75 

T 

Leu 

76 

C 

A 

C C A N G C T C 

Thr 

74 

Thr/Met 

75 

Leu 

76 

A 

C C A T G C T C 

Thr 

74 

Met 

75 

Leu 

76 

Proteasomal Activity 

actin

SHORT Syndrome 

Autosomal dominant (n=4) and recessive (n=11) 

• Short stature 

• Hyperextensibility of 

joints 

• Ocular depression 

• Rieger anomaly 

• Teething delay 

• Premature onset of DM 

• Lipodystrophy 

AD, type 1 AD, type 2

SHORT 1100 

Photos from Dr. Al-Gazali, UAE

SHORT 1100 

1 2 

3 

4 5 6 7

SHORT 1100 

• Exome sequencing 3 affected subjects 

• Filters: 

• Linkage region 

• Functional variants 

• Not in 1000G and dbSNP 

• 5 variants left (none in Seattle Exome Project) 

• One of them is a good candidate

Neonatal Progeroid Syndrome 

(Wiedemann-Rautenstrauch) 

• Premature birth 

• Oligoohydroamnios and IUGR 

• Dry, deeply wrinkled skin 

• Large, low set ears, and beaked nose 

• Generalized loss of SC fat sparing gluteal region 

• Normal glucose and lipids 

• 25 patients reported, early death

NPS 100.3 

O’Neill, Simha, et al. AJMG 143A:1421-30, 2007

Neonatal Progeroid Syndrome 

(Wiedemann-Rautenstrauch)


Disorders of Adipose Tissue Development, Differentiation and Death 

Development Differentiation Death/Apoptosis 

Interstitial tissue 

(PSMB8) 

Myocytes 

Osteoblasts 

Transcription 

factors? 

Adipogenic factors 

(Insulin, cortisol, etc.) 

C/EBPβ 

C/EBPδ 

C/EBPα 

SREBP1c 

PPARγ / RXRα 

Lipogenesis 

(FAS, ACC, 

GPAT, AGPAT, DGAT) 

Apoptosis 

(Lamin A/C, 

ZMPSTE24) 

Feeding 

Seipin/AKT2 

Fasting 

Mesenchymal 

Stem cells 

Pre-adipocyte 

Adipocyte Mature adipocyte Cell Death 

Garg. JCEM 2011;96:3313-25


Disorders of Lipid Droplet Formation 

Caveolae 

Nucleus 

Lamin A/C 

(ZMPSTE24) 

Caveolin-1 

(PTRF) 

Caveolin 

vesicle 

Nuclear 

Lamina 

ER 

FA-CoA 

CoA 

Glycerol-3-P 

LPA 

FA-CoA 

CoA AGPATs 

Pi 

PA 

Lipid droplet 

DAG 

MGATs 

FA-CoA 

CoA 

DGATs 

TG 

GPATs 

PAPs 

CoA FA-CoA 

MAG 

CIDEC 

Perilipin1 

Seipin 

Garg. JCEM 2011;96:3313-25

Leptin Therapy in Patients with 

Lipodystrophy 

• 9 Females 

- 5 Congenital Generalized Lipodystrophy 

- 3 Acquired Generalized Lipodystrophy 

- 1 Familial Partial Lipodystrophy 

• 2 Sites 

- NIH - UT Southwestern 

• Oral EA et al. NEJM 346:570-8; 2002

Hypoglycemic Therapy During Leptin Study 

Patient baseline period 4mo of leptin therapy 

NIH-1 

Metformin (500mg bid) 

Acarbose (50mg tid) 

None 

NIH-2 

NIH-3 

NIH-4 

NIH-5 

NIH-6 

NIH-7 

UTSW-1 

Insulin (800 U/day) 


Metformin (500mg tid) 



Metformin (500mg tid) 


Pioglitazone (45mg qd) 


None 

None 

None 

None 

None 



UTSW-2 1 None 

None 

1 

Nondiabetic patient • Oral EA et al. NEJM 346:570-8; 2002

- 

Leptin Therapy in Patients with Lipodystrophy 

Leptin Dose 

(% Replacement) 

200 

100 

0 

16 

‡ 

Leptin 

(ng/mL) 

12 

8 

4 

* 

0 

1000 

Triglycerides 

(mg/dL) 

800 

600 

400 

* 

‡ ‡ 

200 

0 

0 1 2 3 4 

Study Period (months) 

• Oral EA et al. NEJM 346:570-8; 2002

- 

Leptin Therapy in Patients with Lipodystrophy 

Leptin Dose 

(% Replacement) 

Glucose 

(mg/dL) 

200 

100 

0 

220 

200 

180 

160 

140 

120 

100 

80 

10 

‡ 

Hemoglobin A1c 

(%) 

9 

8 

7 

‡ 

‡ ‡ 

6 

0 1 2 3 4 

Study Period (months) 

• Oral EA et al. NEJM 346:570-8; 2002

Acknowledgments 

Genetics 

• Anil Agarwal, Ph.D. 

• Robert Barnes, M.S. 

• Anne Bowcock, Ph.D. 

• John Peters, B.S. 

• Lynda Bennett, Ph.D. 

• William Gitomer, Ph.D. 

• Chao Xing, Ph.D. 

Radiology 

• Ronald Peshock, M.D. 

• James Fleckenstein, M.D. 

• Paul Weatherall, M.D.


Center for Human Nutrition 

• Dali Chen, M.D. 

• Wasim Haque, M.D. 

• Anoop Misra, M.D. 

• Lalitha Subramanyam, MD 

• Asha Prakash, M.D. • Vinaya Simha, M.D. 

• Maheswari Vinai, M.D. • Claudia Quittner 

• Hamsa Gangaswamiah, M.D. • Hongzhao Ji 

• Aparna Peethambaram, M.D. • Savitha Shastry, M.D. 

• Darshana Purohit, M.D. • Zahid Ahmad, M.D. 

• Aliya Heyliger, M.D. • Scott Grundy, M.D., Ph.D.


Many National and International Collaborators 

Patients and Their Families 

FPL CGL MAD FPLX MDP WRS SHORT APS 

APL 

AGL 

Financial Support from NIDDK and NCRR

For More Information visit: 

FPL CGL MAD FPLX MDP WRS SHORT APS 

APL 

AGL 

www.lipodystrophy.info

Obesity & Lipodystrophy - Medical College of Wisconsin

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