adipose tissue dysfunction in obesity and lipodystrophy
TRANSCRIPT
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 triglyc- erides 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 testos- terone and androstenedione to estrogen and estrone, respectively. TNF-0[ = tumor necrosis fac- tor~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 circu- lation. Addition of 3 acyl (fatty acid) groups to a glycerol moiety occurs in a series of acylation reactions catalyz- ed by 3 acyltransferases, namely, glycerol-3-phosphate acyltransferases (GPATs), 1-acylglycerol-3-phosphate acyl-
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Clinical Cornerstone • ABDOMINAL ADIPOSITY AND CARDIOMETABOLIC RISK • Vol. 8, Supplement 4
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 sub- strates 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 hor- mones, 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, plasmino- gen 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 aro- matase 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; how- ever, several hypotheses have been proposedfl ° First, the adipocytes in obese individuals are already packed, and
patients with lipodystrophies are lacking sufficient adi- pocytes 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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Clinical Cornerstone • ABDOMINAL ADIPOSITY AND CARDIOMETABOLIC RISK • Vol. 8, Supplement 4
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 in- creased FFA flux in patients with obesity or partial lipo- dystrophies. 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 auto- crine products of adipose tissue can profoundly affect normal metabolic homeostasis and probably play an
important role in the development of metabolic compli- cations 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 complica- tions. ~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 obe- sity 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 glu- cose 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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Clinical Cornerstone • ABDOMINAL ADIPOSITY AND CARDIOMETABOLIC RISK • Vol. 8, Supplement 4
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 exam- ple, 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 ener- gy 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, there- fore, 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; there- fore, 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 lipodys- trophy 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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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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