Adipose tissue is important in the maintenance of energy homeostasis. Dysfunction of adipose tissue causes various metabolic disorders. The most common adipose tissue disorder is obesity, which has now become an epidemic disease. Obesity is defined as body mass index greater or equal to 30 kg/m2 and features a massive expansion of white adipose tissue. Although obesity caused by genetic disorders is rare, it has been identified in humans. Patients with leptin deficiency, caused by a homozygous frame shift, nonsense, or missense mutation of the leptin gene, for example, have an undetectable level of leptin in the circulation and develop early-onset severe obesity.1997, 2004, 1998 Metabolic disorders associated with leptin deficiency can be successfully corrected by administration of recombinant human leptin.1999 Loss-of-function mutations in leptin receptor cause similar clinical phenotypes to those of leptin deficient patients.2007, 1998 In other cases, mutations in melanocortin-4 receptor (MC4R), which disrupts normal expression and trafficking of MC4R to the cell surface, account for 5–6% of patients with severe early-onset obesity.2000, 2006 And mutations in POMC, prohormone convertase 1 (PC1), tyrosine kinase receptor tropomycin-related kinase B (TrkB), brain-derived neurotrophic factor (BNDF), or single minded 1 (SIM1) have been found to cause severe obesity in humans.1998, 1997, 2007, 2004, 2006, 2008, 2007
In addition to obesity caused by monogenic mutations, polygenic mutation–related obesity has been described in humans. For example, mutations in more than 14 genes have been identified in Bardet–Biedl syndrome, which is an autosomal recessive disease featuring obesity and other abnormalities such as learning difficulties, retinal dystrophy, renal dysfunction, and hypogonadism.2007, 2003 Lack of gene expression due to imprinting on chromosome 15q11–13 leads to Prader–Willi syndrome, which is characterized by obesity, mental retardation, short stature, hypogonadism, and hypotonia.2008, 2009 Deletion of a 220 kb fragment on chromosome 16p11.2, which includes the SH2B1 gene, is also found to be associated with familial severe early-onset obesity.2010
Sedentary lifestyles and energy-dense diets are the major causes of the obesity epidemic. Humans with low birth weight are also at increased risk for developing obesity and related metabolic disorders. The limited nutrition in the uterus restricts fetal adipose tissue development in order to protect the development of vital organs, and therefore it sensitizes adipose tissue (mainly visceral adipose depot) for fat deposition in the postnatal period when nutrient supply is no longer restrained.2006, 2004 Obesity is a risk factor for the development of many chronic diseases, such as cardiovascular diseases, hypertension, dyslipidemia, nonalcohol fatty liver disease, certain forms of cancer, and, particularly, insulin resistance and type 2 diabetes. The mass of visceral adipose depots, not subcutaneous adipose depots, is positively correlated with obesity-related metabolic disorders. Central obesity can also be caused by chronic exposure to excessive amounts of glucocorticoids, which is the common clinical feature of Cushing syndrome. The elevated levels of glucocorticoids can be either exogenous, from chronic glucocorticoid therapy, or endogenous, from pituitary adenoma, adrenal adenoma, or hyperplasia.2011 Glucocorticoids have been reported to increase appetite and stimulate lipoprotein lipase activity, preferentially in visceral adipose depots.2010 Activity of AMPK, the key cellular energy sensor that represses lipid synthesis, is reduced by 70% in visceral adipose tissue of patients with Cushing syndrome, providing a potential mechanism for glucocorticoid-promoted central obesity.2008
Adipose tissue inflammation
Extensive studies have demonstrated that obesity-related insulin resistance and type 2 diabetes are associated with inflammation in adipose tissue.2006, 2006 In an obese state, massively expanded adipose tissue secretes a variety of inflammatory markers, cytokines, and chemokines at elevated levels. Some of these factors, such as TNF-α, IL-6, IL-1β, and MCP-1, have been reported to impair insulin signaling.1994, 1996, 2003, 2003 Dysregulation of adipocyte lipolysis by increased expression of adipose proinflammatory cytokines contributes to systemic insulin resistance through elevated circulating FFA levels. Multiple types of proinflammatory immune cells have been identified that increase in obese adipose tissue, such as M1 macrophages, neutrophils, CD8+ T lymphocytes, IFN-γ+ Th1 cells, B2 cells, and mast cells (Fig. 4).2012 Anti-inflammatory immune cells that normally exist in the lean adipose tissue, such as M2 macrophages, eosinophils, regulatory T (Treg) cells, and invariant natural killer T (iNKT) cells, are decreased in the obese adipose tissue.2012 The accumulation of activated macrophages in adipose tissue in obesity has been shown to secrete a variety of proinflammatory cytokines and chemokines that potentially contribute to obesity-related insulin resistance.2003, 2009 Diet-induced obese mice with decreased adipose macrophage infiltration or macrophage ablation have reduced expression of inflammatory cytokines in adipose tissue and improved systemic insulin sensitivity.2007, 2006, 2007, 2011 Conditional depletion of proinflammatory macrophages leads to a significant decrease of inflammatory molecules in adipose tissue and rapid normalization of insulin sensitivity.2008 Weight loss in obese subjects has also been associated with decreased macrophage infiltration and a reduction of inflammatory gene expression in adipose tissue.2004, 2005 On the other hand, secretion of insulin-sensitizing adiponection is reduced in obese subjects.2005
Figure 4. Changes of immune cell populations in adipose tissue in obesity. A Th1 response occurs in obese adipose tissue, featured with decreased populations of anti-inflammatory immune cells, including regulatory T (Treg) cells, M2 macrophages, eosinophils, and iNKT cells but increased populations of proinflammatory immune cells, such as neutrophils, M1 macrophages, mast cells, B2 cells, CD8+ T cells, and IFN-γ+ Th1 cells.
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Adipose tissue hypoxia and fibrosis
The initiation of adipose tissue inflammation in obesity is not well understood. It is noteworthy that inflammation is usually associated with pathological adipose tissue enlargement rather than healthy adipose tissue growth.2011 Proper vascularization is needed to support adipose tissue expansion. Rapid expansion of adipose tissue in obesity is often associated with insufficient angiogenesis. Reduced capillary density and blood flow can cause poor oxygenation in expanding adipose tissue. Indeed, hypoxia has been observed in adipose tissue of obese humans and rodents, which is considered to be a potential factor for inducing adipose inflammation.2009, 2009 In primary and cultured adipocytes, hypoxia has been shown to induce expression of many proinflammatory genes such as TNF-α, IL-1, IL-6, MCP-1, macrophage migration inhibitory factor (MIF), and matrix metalloproteinases 2 (MMP2) and 9 (MMP9).2011, 2009 Hypoxia is also a potential contributor to the increase of adipocyte death in obesity, which is linked to the influx of proinflammatory M1 macrophages.2005
Another important factor affecting adipose tissue expansion is the extracellular matrix (ECM) surrounding adipocytes, which mainly contains collagen. ECM components are upregulated in adipose tissue of obese humans and rodents, causing fibrosis, a key feature of adipose tissue dysfunction.2010, 2009 Healthy adipose tissue growth involves newly differentiated small adipocytes, appropriate vascularization, and minimal induction of ECM without causing local inflammation. Pathological adipose tissue expansion mainly occurs through enlargement of existing fat cells, accompanied by insufficient vascularization, macrophage infiltration, and severe fibrosis.2011, 2010 Interestingly, the absence of collegen VI, which is a highly enriched ECM component in adipose tissue, leads to uninhibited adipose expansion and improvement of local inflammation.2009
A proper amount of adipose tissue is critical to metabolic health. Selective loss or improper distribution of body fat, defined as lipodystrophy and lipoatrophy, can cause metabolic disorders, especially insulin resistance and type 2 diabetes. The severity of metabolic disorders is determined by the extent of fat loss. Lipodystrophy can be acquired or genetic (Table 1). Among acquired lipodystrophies, it is well known that HIV patients who undergo long-term highly active antiviral therapy display HIV adipose redistribution syndrome (HARS).1998 HARS is associated with grossly enlarged intraabdominal and neck adipose depots and depletion of subcutaneous adipose depots from the face and extremities, which causes an apple-on-a-stick shape in these patients. HARS occurs in about 50% of HIV patients, who usually also display dyslipidemia and insulin resistance.2011 In lipoatrophic subcutaneous adipose tissue, decreased adipocyte size and apoptosis are observed, which is accompanied by reduced expression levels of adipogenic genes such as PPARγ, C/EBPα, and SREBP-1, suggesting selectively impaired adipogenesis.2006, 2002, 2004 Expression levels of leptin and adiponectin are also reduced, which may contribute to associated insulin resistance. Mitochondrial dysfunction and local inflammation are observed in both lipoatrophic subcutaneous adipose tissue and enlarged visceral adipose tissue, excluding these changes as the mechanism for shrinking subcutaneous fat. This type of lipodystrophy is the most prevalent type among all lipodystrophies.2005, 2000
Table 1. Classification of lipodystrophies
| ||Type||Gene||Clinical features of adipose tissue|
|Acquired lipodystrophies||HIV adipose tissue redistribution syndrome||N/A||Depletion of subcutaneous fat from face and extremities; enlargement of fat depots in abdominal and neck areas|
| ||Lawrence syndrome (acquired generalized lipodystrophy)||N/A||Generalized loss of subcutaneous fat from the face, trunk, abdomen, and extremities; preserved bone marrow and retroorbital fat|
| ||Barraquer-Simons syndrome (acquired partial lipodystrophy)||N/A||Gradual and symmetrical loss of subcutaneous fat from the face, neck, upper extremities and abdomen; preserved fat in lower extremities|
|Genetic lipodystrophies||Berardinelli-Seip syndrome (congenital generalized lipodystrophy)||AGPAT2||Generalized fat loss in subcutaneous, intraabdominal, intermuscular and intrathoracic regions; preserved fat in palms, soles, periarticular and retroorbital regions|
| || ||BSCL2||No body fat at birth|
| || ||Caveolin 1||Similar to AGPAT2 deficiency but has preserved bone marrow fat.|
| || ||PTRF||Similar to AGPAT2 deficiency but has preserved bone marrow fat|
| ||Familial partial lipodystrophy||LMNA||Loss of subcutaneous fat in both extremities and the trunk|
| || ||PPARγ||Loss of subcutaneous fat in the extremities|
| || ||AKT2||Loss of subcutaneous fat in the extremities|
| || ||PLIN1||Loss of subcutaneous fat in the extremities|
| || ||CIDEC||Loss of subcutaneous fat in the extremities|
Other less prevalent types of acquired lipodystrophies include Lawrence syndrome (acquired generalized lipodystrophy, AGL) and Barraquer–Simons syndrome (acquired partial lipodystrophy, APL).2003 Both AGL and APL are early-onset lipodystrophies and affect more females than males. AGL patients suffer from generalized loss of subcutaneous fat, including the face, trunk, abdomen, and extremities, but bone marrow and retroorbital fat are unaffected. APL patients feature gradual subcutaneous fat loss starting from the face and symmetrically spreading downward to the neck, upper extremities, and abdomen, with fat in lower extremities spared. Most AGL patients have hepatic steatosis, hypertriglyceridemia, and diabetes. APL has been found to associate with several autoimmune diseases, such as systemic lupus erythematosus and dermatomyositis.
Genetic lipodystrophies are rare diseases that occur in less than one in a million people and, like acquired lipodystrophies, they are identified in females more often than in males.2011 Berardinelli–Seip syndrome (congenital generalized lipodystrophy, CGL) patients account for about 30% of genetic lipodystrophy cases reported to date. CGL is an autosomal recessive disorder.1954, 1959 Due to near complete absence of body fat, CGL infants are easily recognized at birth. These children have accelerated growth due to strong appetite and often develop diabetes, hyperlipidemia, hepatic steatosis, and polycystic ovaries later in life. Deficiencies of at least four genes have been identified in CGL patients: 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), Berardinelli-Seip congenital lipodystrophy 2 (BSCL2, seipin), caveolin 1 (CAV1), and polymerase I and transcript release factor (PTRF).2002, 2001, 2008, 2009 AGPAT2 is abundantly expressed in adipose tissue, and it catalyzes synthesis of triglycerides and phospholipids by acylating fatty acid at the sn-2 position of glycerol.2009 BSCL2 encodes a protein named seipin, which is essential for proper lipid droplet formation and adipocyte differentiation through maintaining sustained expression of PPARγ and C-EBPα, which are critical for inducing expression of genes involved in triglyceride synthesis, such as AGPAT2, lipin1, and DGAT2.2007, 2008 CAV1 encodes caveolin 1, a protein that resides in cell surface lipid rafts and forms microdomains termed caveolae. Caveolin 1 may mediate fatty acid transport from cell surface to lipid droplets through movement and merging of caveolae vesicles to lipid droplets. PTRF is essential for regulating proper location of caveolins and formation of caveolae.2009 Mutations in AGPAT2 and BSCL2 are the most commonly found ones in CGL patients, while mutations in CAV1 and PTRF are rare. Among the four subtypes of CGL, mutations in BSCL2 produce the most severe phenotype, as patients are born with no body fat. Patients with the other three subtypes of CGL lose fat in subcutaneous, intraabdominal, intermuscular, and intrathoracic regions but have well-preserved adipose tissue in palms, soles, and periarticular and retroorbital regions. Patients with mutations in CAV1 and PTRF also have bone marrow fat preserved.2008, 2010, 2008
In comparison to the Berardinelli–Seip syndrome, familial partial lipodystrophy (FPL) is a less severe form of genetic lipodystrophy, characterized by fat loss in patients starting from childhood, puberty or even a later stage. Five FPL genes have been identified: LMNA (Dunnigan syndrome), PPARγ, AKT2, PLIN1, and CIDEC.2000, 2006, 2004, 2009 LMNA encodes lamins A and C, proteins localized in the nuclear envelope, and dysfunction of lamins may cause adipocytes to die prematurely.2000, 2000 PPARγ is a master transcription factor for adipocyte differentiation, and AKT2 is an important component of insulin signaling; the absence of either PPARγ or AKT2 impairs adipocyte development. PLIN1 encodes perilipin 1. Both perilipin 1 and CIDEC are lipid droplet-coating proteins that protect the droplets from being hydrolyzed. Recent studies indicate that perilipin 1 and CIDEC are also involved in hepatic steatosis and foam cell formation.2011, 2012
FPL caused by mutations in LMNA, PPARγ, AKT2, and PLIN genes is autosomal dominant, while FPL caused by mutation in the CIDEC gene is autosomal recessive. Among the five subtypes of FPL, Dunnigan syndrome (more than 300 patients) is most prevalent, followed by mutations in PPARγ (30 patients), PLIN1 (6 patients), AKT2 (four patients), and CIDEC (1 patient).2011 Dunnigan syndrome is the most severe FPL, characterized by subcutaneous fat loss in both extremities and the trunk. The remaining four subtypes of FPL involve only subcutaneous fat loss in the extremities. FPL patients usually develop diabetes and metabolic disorders in adulthood.
In addition to CGL and FPL, lipodystrophies can also be associated with other genetic diseases, such as MAD (mandibuloacral dysplasia), MDP (mandibular hypoplasia, deafness, and progeroid features), and autoinflammatory syndromes.
Adipose tissue-derived tumors
Abnormal white adipose tissue development can produce tumors. The most common white adipose tumor is lipoma, which is a mobile, soft, and benign tumor that affects approximately 1% of the general population. Lipomas usually occur in people that are 40–60 years old but can also affect children.2002, 2006 Lipomas are commonly observed in subcutaneous tissue between skin and muscle, though they can occur in any part of the body. Lipomas are classified into several subtypes depending on the location of the tumor, and other tissue types coexist with fat. These tumors usually do not cause any symptom and treatment is not necessary in most cases. Surgical removal is needed in some cases if the location or the size of lipomas cause pain or other problems. Lipomas may begin to grow after a tissue injury or trauma, and they tend to run in families. Human studies showed that a C-terminally truncated HMG I-C product with three DNA binding domains fused to other gene products is frequently found in lipomas. Transgenic mice overexpressing the three DNA domains of HMG I-C fused to various proteins have increased neonatal adipose tissue growth and a high incidence of lipomas, indicating that the C-terminally truncated HMG I-C protein maybe important in promoting lipoma formation.2000
White adipose tissue can also develop into malignant liposarcoma, which mostly occurs in deep soft tissue and accounts for about 20% of all mesenchymal malignancies.2000 Liposarcoma is divided into several subtypes based on the extent of cell differentiation and cell morphology: well-differentiated, dedifferentiated, myxoid, round cell, and pleomorphic liposarcomas. Well-differentiated liposarcoma accounts for 40–45% of liposarcomas with equal occurrence in the limbs and the retroperitoneum. This type of liposarcoma has approximately a 30% chance of local recurrence but does not metastasize. Dedifferentiated liposarcoma is characterized with a loss of lipogenic morphology in well-differentiated liposarcoma, occurring 90% of the time in the primary tumor and 10% of the time in recurrences. Dedifferentiation is accompanied by a 15–20% metastatic rate. Myxoid and round cell liposarcomas tend to occur in the limbs, and they represent 30–35% of liposarcomas. Pleomorphic sarcoma is the rarest aggressive subtype and tends to be observed in the limbs with a 30% metastatic rate.
Brown adipose tissue can also form tumors called hibernomas, which are rare and slow-growing benign tumors. The name derives from the morphologic similarity between the tumor and hibernating glands of animals.1949 Hibernomas tend to occur in the thigh, shoulder, interscapular area, neck, chest, axilla, abdominal cavity, and retroperitoneum.2001 Hibernomas most frequently occur in people in their thirties and affect females more often than males.2010 The tumors are well encapsulated, soft, and mobile, and they are highly vascularized and composed of a mixture of brown and white adipocytes. A typical hibernoma contains more than 70% brown adipocytes—the color varying from tan to brown. Patients usually have no symptoms from the tumor itself unless its mass affects adjacent structures. It remains to be explored whether hibernomas affect energy homeostasis in humans.