Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 66

Adipose: Tissue Function

Adipose: Tissue Function

16

18

Adipose: Tissue Function

The parenchyma of adipose tissue consists of adipocytes suspended in a connective tissue matrix, which functions as both a crucial endocrine organ as well as a site for metabolic activity. Two types of adipose tissue have been identified: brown and white. Brown adipose tissue (BAT) in humans is present at birth and provides non-shivering heat generation, while white adipose tissue (WAT) is present in adults and is a highly metabolic, endocrine organ. Pathology can occur both from adipose tissue deficiency as well as excess.

Brown Adipose Tissue (BAT)

Non-shivering thermogenesis. Brown adipocytes utilize oxygen and lipids as substrates to produce heat. The functional thermogenic unit consists of a brown adipocyte maintained within a structural network of connective tissue with access to a rich blood supply and innervation. The vascular network serves the BAT by both delivering substrate and signaling molecules to the organ as well as carrying away the heat product to the body. Therefore, access to an ample vascular network is necessary in order to achieve maximal generation and distribution of the BAT-generated heat. Heat generation is achieved by a mitochondrial protein known as uncoupling protein-1 (UCP1) or thermogenin. It allows for combustion of fatty acids in the respiratory chain without the production of ATP; instead, heat is the form of energy that is released.

Signal transmission. The ventromedial (VML) hypothalamic nucleus of the brain coordinates information regarding body energy reserves and body temperature. When a thermogenic demand is sensed by the VML, the information is relayed via the sympathetic nervous system. The neurotransmitter norepinephrine (NE) is released and binds β-3 adrenergic receptors in the BAT to trigger an intracellular cascade that eventually leads to the generation of heat and an increased body temperature.

Thermogenic demand. Pre-adipocytes represent a rapidly accessible stem cell population that can replicate and differentiate into mature BAT under situations of increased thermogenic demand.

White Adipose Tissue (WAT)

Steroid hormone metabolism. Adipose tissue serves a crucial role in processing steroid hormones produced in the adrenal glands and gonads. This processing is referred to as “tissue-specific pre-receptor steroid hormone metabolism” and is necessary for full activation or inactivation of the circulating steroid hormones. The enzymes required to perform this process are extensive and include cytochrome P450-dependent aromatase, 3β-hydroxysteroid dehydrogenase (HSD), 3αHSD, 11βHSD1, 17βHSD, 17α-hydroxylase, 5α-reductase, and UDP-glucuronosyltransferase 2B15.

Aromatase is an especially important adipose enzyme in that it converts androgens into estrogens. In postmenopausal women, gonadal synthesis of estrogens becomes diminished and adipose tissue accounts for all of the circulating estrogen.

Reservoir for energy storage. Despite the large capacity of adipose tissue to secrete proteins and metabolize steroid hormones, the major secretory product of WAT is fatty acids. Adipocytes store triglycerides internally as a lipid droplet through an enzymatic process. First, triacylglycerides absorbed from the diet or synthesized in the liver reach their storage site (adipose tissue) and are converted into fatty acids via the enzyme lipoprotein lipase (LPL). They are then combined with the metabolic glucose product glycerol phosphate to reform triacylglyceride inside the adipocyte. When the cell receives signals that the body requires use of the free fatty acids for energy, they are then broken down via an enzyme called hormone sensitive lipase (HSL) that breaks apart the stored triglycerides to release free fatty acids. HSL responds to hormones such as catecholamines and glucagon to increase the free fatty acid concentration in the plasma so that it can be utilized for energy. Therefore, the sympathetic nervous system is a primary modulator of triacylglycerol breakdown.

Endocrine functions. Adipose tissue as an organ consists of several different tissue types including adipocytes, connective tissue, nerves, stromovascular cells, and immune cells. These tissues function in synchrony to express and secrete several hormonal and non-hormonal products including leptin, angiotensinogen, adipsin, acylation-stimulating protein, retinol-binding protein, tumor necrosis factor alpha (TNFα), interlukin-6, plasminogen activator inhibitor-1, adiponectin, complement components, and resistin. Several of these mediators are discussed below.

Secreted proteins.

1 Leptin is a polypeptide (16-kDa) containing 167 amino acids and has a structural configuration similar to that of cytokines. Although leptin can be synthesized in several sites of the body including the stomach, placenta, and mammary glands, the predominant site of its synthesis is in WAT. The primary role of leptin is to serve as a messenger to the body that the level of energy is at a sufficient state. Therefore, adipose tissue mass and nutritional status are the main mediators of leptin and directly correlate to circulating levels. These levels rapidly decline with caloric restriction and weight loss. Leptin can also be modulated by other chemical mediators: it is increased by insulin, steroids, and TNFα, and is decreased by β3-adrenergic activity, androgens, free fatty acids, growth hormone (GH), and peroxisome proliferator-activated receptor-γ agonists.

2 Genetically modified mice that have a recessive knockout of the leptin gene are referred to as ob/ob mice and are profoundly obese. The lack of circulating leptin leads to an absent detection of energy sufficiency and causes the mice to eat to excess. Therefore these mice are often applied as research models for type 2 diabetes.

3 TNFα is a transmembrane protein (26-kDa) that becomes biologically active after cleavage. Levels of TNFα positively correlate with obesity and insulin resistance. Induction of insulin resistance can be achieved in vitro and in vivo via chronic TNFα exposure.

4 Interleukin-6 (IL-6) is similar to TNFα in that it is a cytokine produced by adipose tissue that also is associated with obesity and insulin resistance, and circulating levels have been shown to decrease with weight loss. It also serves as a predictor of type 2 diabetes as well as cardiovascular disease.

Adipose tissue excess (obesity). Associations of obesity are referred to as metabolic syndrome and are characterized by insulin resistance, hyperglycemia, dyslipidemia, hypertension, and prothrombotic and proinflammatory states.

Adipose tissue deficiency (lipodystrophy). A deficiency of adipose is also associated with characteristics of metabolic syndrome.

Krishna S. Vyas

Christopher Areephanthu

University of Kentucky College of Medicine

See Also: Adipose: Cells Types Composing the Tissue; Adipose: Current Research on Isolation or Production of Therapeutic Cells; Adipose: Development and Regeneration Potential; Adipose: Existing or Potential Regenerative Medicine Strategies; Adipose: Major Pathologies; Adipose: Stem and Progenitor Cells in Adults.

Further Readings

Cannon, B. and Jan Nedergaard. “Brown Adipose Tissue: Function and Physiological Significance.” Physiological Reviews, v.84/1 (January 1, 2004).

Kershaw, E. E. and J. S. Flier. “Adipose Tissue as an Endocrine Organ.” Journal of Clinical Endocrinology and Metabolism, v.89 (2004).

Trayhurn, P. and J. H. Beattie. “Physiological Role of Adipose Tissue: White Adipose Tissue as an Endocrine and Secretory Organ.” Proceedings of the Nutrition Society, v.14/3 (2001).