Adipose tissue dysfunction in obesity and lipodystrophy

Clinical Cornerstone • ABDOMINAL ADIPOSITY AND CARDIOMETABOLIC RISK • Vol. 8, Supplement 4

Free FattyAcids

LPL

Figure I.

H ~ GI] ~ Androgens

Free . Estrogens Fatty A c ~ Y -"

keptin

The main function of adipocytes is storage of energy as triglycerides and release of energy as free fatty acids (FFAs) and glycerol. Biosynthesis of triglycerides involves a series of acylation reactions at the 3 positions of glycerol-3-phosphate using various acyltransferases. Glycerol-3- phosphate is generated from glycolysis, and acyl coenzyme A (acyI-CoA) is generated from F FAs using acyI-CoA synthetase. FFAs are mainly produced during hydrolysis of circulating triglycerides by lipoprotein lipase (LPL). Hormone-sensitive lipase (HSL) plays the major role in releasing energy from the adipocytes by hydrolyzing triglycerides into glycerol and FFAs. Adipocytes also secrete a variety of peptide hormones called adipocytokines (eg, leptin, adiponectin, resistin), which play a role in energy regulation. Another function of adipocytes is to aromatize testosterone and androstenedione to estrogen and estrone, respectively. TNF-0[ = tumor necrosis factor~alpha; PAl-1 = plasminogen activator inhibitorq; IL-6 = interleukin-6; angptl-4 = angiopoietin- like protein 4.

major producers of LPL, synthesize and secrete LPL, which then migrates to the capillary endothelial lumen. LPL is bound to the glycocalyx of the endothelial plasma membranes, where it hydrolyzes circulating triglycerides from very-low-density lipoproteins and chylomicrons to produce FFAs, which are taken up by the adipocytes, both passively and actively, for re-esterification with ~olycerol-3-phosphate ~ • ~ 4 into tri~lycerldes-' (Figure 1).

Of the 2 important substrates involved in triglyceride biosynthesis in adipose tissue, glycerol-3-phosphate is a product of glycolysis, and acyl coenzyme A (acyl-CoA) is formed from FFAs that have been taken up from circulation. Addition of 3 acyl (fatty acid) groups to a glycerol moiety occurs in a series of acylation reactions catalyzed by 3 acyltransferases, namely, glycerol-3-phosphate acyltransferases (GPATs), 1-acylglycerol-3-phosphate acyl-

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transferases (AGPATs), and diacylglycerol acyltrans-

ferases (DGATs). Each enzyme has 2 or more known iso- forms.5 9 AGPATs catalyze the acylation of lysophospha-

tidic acid to form phosphatidic acid 1° (Figure 1). Many

phospholipids (eg, phosphatidylinositol, phosphatidyl- glycerol, cardiolipin, phosphatidylcholine, phosphatidyl- ethanolamine, phosphatidylserine) are also formed from

phosphatidic acid and diacylglycerol as products of the same biosynthetic pathway. These phospholipids are inte- gral components of all cell membranes and play a role as

second messengers in various intracellular signaling events. 11

Lipolysis in adipocytes is regulated by hormone- sensitive lipase (HSL). 12 This intracellular enzyme

hydrolyzes triglyceride stores in the adipocytes and releases FFAs and glycerol into circulation as fuel for the

whole body. FFAs released from adipose tissue con- tribute energy required by the skeletal muscles and substrates for triglyceride biosynthesis in the hepatocytes.

Glycerol, on the other hand, contributes to gluconeo- genesis in the liver or kidneys. The 2 major hormones regulating HSL are insulin and the catecholamines. 12'13

In addition, glucocorticoids, sex hormones, thyroid hormones, growth hormones, and, possibly, glucagon partic- ipate in the regulation of lipolysis by modulating receptor

activity for insulin and the catecholamines. Other extra- hormonal factors, such as diet, trauma, and exercise, may also play a role in the regulation of HSL-mediated

adipocyte lipolysis.

K E Y P O I N T

Adipocytes secrete peptide hormones

called adipocytokines, which help regulate

food intake, energy expenditure, and fuel

metabolism.

19 of the steroid molecule, and aromatization of the A ring of the steroid. Both adipocytes and stromal cells of adipose tissue express aromatase. Although adipose tis-

sue aromatization is trivial in healthy adult men and women, with increasing body weight in older men and postmenopausal women, this pathway can have a sub- stantial effect on estrogen levels. 16

D y s f u n c t i o n of A d i p o s e T i s sue

Excess adipose tissue in patients with generalized or regional obesity and markedly reduced adipose tissue in patients with genetic or acquired lipodystrophy are both

associated with insulin resistance and its complications (eg, type 2 diabetes, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol [HDL-C], and hepatic steatosis).17 19 Thus, early recognition of such patients,

who are predisposed to metabolic complications, is critical to reducing disease burden.

Adipocytokine Secretion Adipocytes secrete a variety of peptide hormones called

adipocytokines. The secreted peptides include hormones (leptin, adiponectin, resistin), cytokines (interleukin-6 and

-8, tumor necrosis factor-ct), enzymes (LPL, plasminogen activated inhibitor-l), and complement factors (adipsin, complement factor C3). 14 Adipocytokines play

a role in regulation of food intake, energy expenditure, fuel metabolism, and a variety of other physiologic processes.

Aromatization Extraglandular conversion of testosterone and andro-

stenedione to estrogen and estrone, respectively, occurs principally in adipose tissue and is catalyzed by aromatase enzymes. 15 The steps involve sequential hydrox-

ylation, oxidation, removal of the carbon at position

K E Y P O I N T

Excess adipose tissue in obesity and

markedly reduced adipose tissue in

lipodystrophy are both associated with

insulin resistance and its complications.

The underlying mechanisms by which adipose tissue

disorders cause insulin resistance remain unclear; however, several hypotheses have been proposedfl ° First, the adipocytes in obese individuals are already packed, and

patients with lipodystrophies are lacking sufficient adipocytes and therefore have a limited capacity to store fat in nonlipodystrophic adipose tissue. This limitation of

triglyceride storage may result in aberrant storage of

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triglycerides in other organs, such as the liver (hepatic

steatosis) and skeletal muscles (muscle steatosis), result- ing in hepatic and peripheral insulin resistance. Another hypothesis relates to reduced glucose uptake by skeletal

muscle and increased hepatic glucose output due to increased FFA flux in patients with obesity or partial lipodystrophies. However, this mechanism may not be impli-

cated in individuals with generalized lipodystrophy, as they may have reduced FFA flux. A third hypothesis per- tains to the role of adipocytokines, the secretory products

of adipose tissue, in causing insulin resistance. Over the past decade it has become clear that adipose

tissue secretes a variety of hormones, cytokines, growth

factors, and other peptides that are capable of influencing local adipocyte biology as well as distant organ systems, such as the central nervous system, liver, pancreas, and

skeletal muscles. These endocrine, paracrine, and autocrine products of adipose tissue can profoundly affect normal metabolic homeostasis and probably play an

important role in the development of metabolic complications in adipose tissue disorders. For example, patients with generalized lipodystrophies have deficiencies of lep-

tin and adiponectin, which may be related to severe insulin resistance. 2° Interestingly, leptin replacement therapy markedly improved metabolic complications, including

hepatic and skeletal muscle steatosis, in severely hypoleptinemic patients with lipodystrophies. 2L22

tic ovary syndrome, and hyperuricemia) without being overtly obese. 19'24 In obese patients, the amount of ex-

cess adipose tissue, as well as excess adipose tissue located in the subcutaneous truncal region and, possibly,

the intra-abdominal region, determine the prevalence and severity of insulin resistance and its associated complications. ~7,~s In contrast, among patients with lipodystro-

phies, the extent of adipose tissue loss is the major deter- minant of insulin resistance and its complications. Nonetheless, the underlying mechanisms causing insulin

resistance and metabolic syndrome in patients with obesity and lipodystrophies may be similar (Figure 27. For example, in patients with severe forms of obesity and

lipodystrophies, there may be a limitation in storage of triglycerides in adipose tissue that results in diversion of triglycerides to aberrant sites (eg, the liver and skeletal muscles) and development of insulin resistance. 19'25

K E Y P O I N T

The underlying mechanisms causing insu-

lin resistance and metabolic syndrome in

patients with obesity and lipodystrophies

may be similar.

K E Y P O I N T

Endocrine, paracrine, and autocrine prod-

ucts of adipose tissue affect metabolic

homeostasis and probably play important

roles in the development of metabolic

complications in adipose tissue disorders.

Although defining metabolic syndrome using criteria

for generalized or regional adiposity such as body mass index and waist circumference 23 may be appropriate for

the population at large, patients with lipodystrophy may

develop metabolic syndrome and complications related to insulin resistance (eg, type 2 diabetes, impaired glucose tolerance, hypertriglyceridemia, low levels of

HDL-C, hepatic steatosis, acanthosis nigricans, polycys-

Lipodystrophies may be caused by genetic or acquired causes. Subtypes have been classified according to phe- notypic and genotypic features (Table) , 19 and the preva-

lence of various components of metabolic syndrome varies among the different subtypes. 19 It is interesting to note that although patients with lipodystrophies have an

increased prevalence of type 2 diabetes, dyslipidemia, and hepatic steatosis, a clear increase in the prevalence of hypertension has not been described. Hypertension

has usually been reported after the onset of diabetic nephropathy. 19

Recent insights into the molecular mechanisms

underlying various types of genetic lipodystrophies have added to our understanding of adipocyte biology and have revealed potential pathways that may be

implicated in causing insulin resistance. ~° Detailed reviews of advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or

other bases of various types of genetic and acquired

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B. Obesity A. Normal C. Lipodystrophy

L I V ~ [ " I ' I U ;SCIr~ L I V t : ~ I I " I LI ~ I,.It:~ L i v e r " I V l U S C l e

Figure 2. The role of adipocytes in tr iglyceride metabolism. [A ] Under normal conditions, there is ample room wi th in adipocytes to store excess d ietary t r ig lycer ides (TGs); therefore, fewer TGs are directed to l iver and skeletal muscles. Under states of energy depr ivat ion (eg, fasting, s tarvat ion) , stored TGs are released f rom adipocytes to del iver free fat ty acids (FFAs) to the liver, skeletal muscle, and o ther organs. [B] In individuals w i th general ized or regional obesity, adipocytes become enlarged, resul t ing in a l im i ta t ion in adipocyte storage capacity and, potential ly, a relat ive block in the disposal of excess d ietary TGs to adipocytes. TGs may then be directed for storage to ectopic sites, such as the l iver and skeletal muscles. Lipolysis of excess TGs may also cont r ibu te to increased FFA flux, f u r the r cont r ibu t ing to TG storage in ectopic sites. [C ] In individuals w i th general ized or part ia l lipodystrophies, there is an absolute or relat ive lack of available adipocytes to s tore TGs; there fore , disposal of excess d ie ta ry TGs in to adipocytes is l im i ted , and TGs are d i rec ted fo r storage to ectopic sites, such as the l iver and skeletal muscles. FFA f lux f rom adipocytes may not be increased, par t icu lar ly in pat ients w i th general ized l ipodystrophies. N = normal ; J" = increase; $ = decrease.

lipodystrophies have been published. 1°'11"19"24"26 29 These

advances may eventually be used to unravel the mecha-

nisms by which common forms of obesity induce insulin resistance.

The rapeu t i c Op t i ons fo r

Ad ipose Tissue Dys func t ion

Diet and Exercise Since common mechanisms may be involved in

inducing insulin resistance in patients with obesity or lipodystrophies, the therapeutic options that are current-

ly available may be useful for treating both conditions; however, modifications may need to be made. For example, reduction of energy intake, particularly dietary tri-

glycerides or dietary fat, may be useful to avoid ectopic triglyceride deposition in the liver and skeletal muscles. Yet excess consumption of carbohydrates can also induce

de novo lipogenesis; therefore, overall reduction in energy intake may help mitigate metabolic complications of both obesity and lipodystrophy. But patients with gener-

alized lipodystrophies, particularly children, have vora-

cious appetites that are difficult to control. Children also require energy for growth and development. Diet, therefore, should be monitored but must also allow for ade-

quate growth in young patients. Similarly, increasing energy expenditure with daily

physical activity, particularly aerobic exercise, can

improve metabolic complications in both obesity and lipodystrophy.

Medication Diabetic patients should be aggressively managed

with oral antihyperglycemic drugs or insulin, since

many of these individuals are at risk of developing long-term complications. Metformin improves insulin sensitivity, reduces appetite, and can induce ovulation

in patients with polycystic ovary syndrome, which is more prevalent in obesity and lipodystrophies; therefore, it should be a drug of choice for these conditions.

The efficacy of metformin, however, has not been stud- ied in patients with genetic or acquired lipodystrophies. Although thiazolidinediones can reduce hepatic steato-

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Clinical Cornerstone • ABDOMINAL ADIPOSITY A N D CARDIOMETABOLIC RISK • Vol. 8, Supplement 4

TABLE. C L A S S I F I C A T I O N O F L I P O D Y S T R O P H I E S .

Genetic Lipodystrophies

Autosomal Recessive Syndromes

Congenital generalized lipodystrophy (CGL) CGL type 1:AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) mutations CGL type 2:BSCL2 (Beraxdinelli-Seip congenital lipodystrophy 2) mutations Other varieties

Mandibuloacral dysplasia-associated lipodystrophy (MAD) Type A, partial lipodystrophy: LMNA (lamin A/C) mutations Type B, generalized lipodystrophy: ZMPSTE24 (zinc metalloproteinase) mutations

SHORT syndrome-associated lipodystrophy Neonatal progeroid syndrome-associated lipodystrophy

Autosomal Dominant Syndromes

Familial partial lipodystrophy (FPL) Dunnigan type (FPLD): LMNA (lamin A/C) mutations FPL associated with PPARG (peroxisome proliferator-activated receptor gmnma [7]) mutations FPL associated with AKT2 (v-AKT murine thymoma oncogene homolog 2) mutations Other varieties

SHORT syndrome-associated lipodystrophy Hutchinson-Gilford syndrome (progeria)-associated lipodystrophy Pubertal-onset generalized lipodystrophy due to LMNA mutations

Acquired Lipodystrophies

Acquired generalized lipodystrophy (AGL) Acquired partial lipodystrophy Localized lipodystrophies Lipodystrophy in HIV-infected patients

SHORT = short stature, hyperextensibility of joints or inguinal hernia, ocular depression. Rieger anomaly, and teething delay• Adapted with permission. 1°

sis, these agents should be used with caution because

they can induce weight gain.

Fibrates are the drugs of choice for treating hypertri-

glyceridemia. Some patients may also require omega-3

polyunsaturated fatty acids from fish oils. Combination

therapy with fibrates and statins may be used, but this

regimen is associated with a higher risk of myopathy.

Niacin is not a drug of choice, as it induces insulin resis-

tance and can exacerbate • ~0 hyperglycerma.- In women

with lipodystrophies, estrogens should be used with cau-

tion because such therapy can exacerbate hypertriglyc- • • q l eridemia and induce acute pancreatltlS.-

Recent data about the efficacy of SC recombinant

leptin in improving hyperglycemia, dyslipidemia, and

hepatic steatosis in patients with hypoleptinemic lipodystrophy seem to be promising. 21'32'33 Leptin therapy

reduced appetite and resulted in a mean weight loss of

4 kg over a 4-month period, which could be one of the

mechanisms by which this treatment may improve meta-

bolic complications in patients with lipodystrophiesfl 1

However, leptin therapy has not been efficacious in obese

patients, and it remains investigational.

C O N C L U S I O N S

Under normal conditions, adipose tissue actively partici-

pates in the storage and release of energy in the form of

triglycerides, as well as the regulation of food intake,

energy expenditure, and fuel metabolism through its

secretory products. Limitation in the capacity of adipose

tissue to store triglycerides and abnormal synthesis of

adipocytokines, however, may be related to the patho-

genesis of insulin resistance and its complications in

patients with adipose tissue disorders such as obesity or

lipodystrophy.

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Clinical Cornerstone • ABDOMINAL ADIPOSITY A N D CARDIOMETABOLIC RISK • Vol. 8, Supplement 4

R E F E R E N C E S 1. Abate N, Garg A. Heterogeneity in adipose tissue metabo-

lism: Causes, implications and management of regional adiposity. Prog Lipid Res. 1995;34:53-70.

2. Eckel RH. Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Meal. 1989;320:1060-1068.

3. Scow RO, Blanchette-Mackie EJ. Why fatty acids flow in cell membranes. Prog Lipid Res. 1985;24:197-941.

4. Abumrad N, Harmon C, Ibrahimi A. Membrane transport of long-chain fatty acids: Evidence for a facilitated process. J Lipid Res. 1998;39:2309-2318.

5. Leung DW. The structure and functions of human lysophosphatidic acid acyltransferases. Front Biosci. 2001; 6:d944-d953.

6. Bell RM, Coleman RA. Enzymes of glycerolipid synthesis in eukaryotes. Annu Rev Biochem. 1980;49:459-487.

7. Hammond LE, Gallagher PA, Wang S, et al. Mitochon- drial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol Cell Biol. 2002;22:8204-8214.

8. Cases S, Smith S J, Zheng YW, et al. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A . 1998;95:13018-13023.

9. Cases S, Stone S J, Zhou P, et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem. 2001 ;276:38870-38876.

10. Garg A. Acquired and genetic lipodystrophies. N Engl J Med. 2004;350:1220-1234.

11. Agarwal AK, Barnes RI, Garg A. Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord. 2004;28:336-339.

12. Hales CN, Luzio JP, Siddle K. Hormonal control of adipose- tissue lipolysis. Biochem Soc Syrup. 1978;43:97-135.

13. Bjorntorp P, Ostman J. Human adipose tissue dynamics and regulation. Adv Metab Disord. 1971;5:277-327.

14. Haque WA, Garg A. Adipocyte biology and adipocytokines. Clin Lab Med. 2004;24:217-234.

15. Simpson ER, Zhao Y, Agarwal VR, et al. Aromatase expression in health and disease. Recent Prog Horm Res. 1997;52:185-213; discussion 213-214.

16. Misso ML, Jang C, Adams J, et al. Adipose aromatase gene expression is greater in older women and is unaffect- ed by postmenopausal estrogen therapy. Menopause. 2005;12:210-215.

17. Abate N, Garg A, Peshock RM, et al. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes. 1996;45:1684-1693.

18. Abate N, Garg A, Peshock RM, et al. Relationship of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88-98.

19. Garg A, Misra A. Lipodystrophies: Rare disorders causing metabolic syndrome. Endocrinol Metab Clin N Am. 2004; 33:305-331.

20. Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab. 2002;87:2395-2398.

21. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570-578.

22. Simha V, Szczepaniak LS, Wagner AJ, et al. Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care. 2003;26:30-35.

23. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001 ;285:2486-2497.

24. Garg A. Lipodystrophies. Ant J Med. 2000;108:143-152. 25. Garg A, Misra A. Hepatic steatosis, insulin resistance, and

adipose tissue disorders. J Clin Endocrinol Metab. 2002; 87:3019-3022.

26. Garg A, Misra A. Lipodystrophies and diabetes. In: DeFronzo RA, Ferrannini E, Keen H, et al, eds. International Textbook o f Diabetes Mellitus. 3rd ed. New York, NY: Wiley; 2004:655-672.

27. Agarwal AK, Garg A. Congenital generalized lipodystrophy: Significance of triglyceride biosynthetic pathways. Trends EndocrhTol Metab. 2003;14:214-221.

28. Agarwal AK, Garg A. Seipin: A mysterious protein. Trends Mol Med. 2004; 10:440-444.

29. Chen D, Misra A, Garg A. Lipodystrophy in human immuno- deficiency virus-infected patients. J CIb7 Endocrinol Metab. 2002;87:4845-4856.

30. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA. 1990;264:723-726.

31. Haque WA, Vuitch 1 v, Garg A. Post-mortem findings in familial partial lipodystrophy, Dunnigan variety. Diabetes Med. 2002;19:1022-1025.

32. Simha V, Szczepaniak LS, Wagner A, et al. Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care. 2003;26:30-35.

33. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clh7 hn,est. 2002;109:1345-1350.

Address correspondence to: Abhimanyu Garg, MD, Professor of Internal Medicine, Chief, Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052. E-mail: [email protected]

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Adipose tissue dysfunction in obesity and lipodystrophy

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