9. Adipose Tissue

uncoupling protein (UCP-1)

-non-shivering thermogenesis -no energy is captured as ATP, only as heat -Leakage - allow H+ to leak through ***brown fat in babies *** small mammals Clinical observations confirm that under normal conditions, brown adipose tissue can expand in response to increased blood levels of norepinephrine. This becomes evident in patients with pheochromocytoma, an endocrine tumor of adrenal medulla secreting excessive amounts of epinephrine and norepinephrine. In these individuals, the UCP-1 gene is activated by norepinephrine stimulation, which also protects brown adipocytes by inhibiting apoptosis. In the past, it was thought that uncoupling proteins were expressed only in brown adipose tissue. Recently, several similar uncoupling proteins have been discovered in other tissues. UCP-2 is linked to hyperinsulinemia and obesity and may be involved in regulation of body weight. UCP-3 is expressed in skeletal muscles and may account for the thermogenic eff ects of thyroid hormone. UCP-4 and -5 are brain mitochondrial- specifi c molecules.

Prader-Willi Syndrome

A genetic mutation in chromosome 15 causes _______________, in which an overproduction of ghrelin leads to morbid obesity. In individuals with this syndrome, compulsive eating and an obsession with food usually arise at an early age. The urge to eat in these individuals is physiologic, overwhelming, and very difficult to control. If not treated, these individuals often die before age 30 of complications attributable to obesity.

hibernomas

Fetal lipomas of brown fat

white (unilocular) adipose tissue

It forms a fatty layer of the subcutaneous (superficial) fascia called the panniculus adiposus Since the thermal conductivity of adipose tissue is only about half that of skeletal muscle, the subcutaneous fascia provides a significant thermal insulation against cold by reducing the rate of heat loss. In the lactating female, mammary fat pad plays an important role in supporting breast function. It provides lipids and energy for milk production, but it is also a site for the synthesis of different growth factors that modulate responses to different steroid and proteins and hormones acting on mammary gland function.

brain-gut-adipose axis

It is almost impossible to separate regulation of adipose tissue from digestive processes and functions of the central nervous system. These interconnected hormonal and neural signals emanating from the adipose tissue, alimentary tract, and central nervous system form the brain-gut-adipose axis that regulates appetite, hunger, satiety, and energy homeostasis

Brown adipose tissue

The cells of ________ adipose tissue are smaller than those of white adipose tissue. The cytoplasm of each cell contains many small lipid droplets, hence the name multilocular, as opposed to white unilocular adipocytes, which contain only one huge lipid droplet differentiate from mesenchymal stem cells under the control of PRDM16/PGC-1 transcription factors.

Peptide YY

The small, 36-amino-acid long gastrointestinal hormone__________ is produced by the small intestine and plays an important role in promoting and maintaining weight loss by inducing a greater sense of fullness soon after a meal. It also acts through receptors in the hypothalamus that suppress appetite. It decreases food intake in individuals by inducing satiety or a sense of fullness and the desire to stop eating. In experimental clinical studies, the infusion of PYY into humans has been shown to reduce food intake by 33% over a period of 24 hours.

Thermogenic activity of brown adipose tissue is facili- tated by

The unique large, round mitochondria in the cytoplasm of brown adipose tissue cells contain uncoupling protein (UCP-1), which uncouples the oxidation of fatty acids from the production of ATP.

Fibrolipoma

Tumor that contains a significant amount of fibrous CT with fat

Angiolipoma

Tumor that contains numerous small blood vessels with fat

Structure of Adipocytes and Adipose Tissue

Unilocular adipocytes are large cells, sometimes 100 um or more in diameter. Adipose tissue is richly supplied with blood vessels, and capillaries are found at the angles of the meshwork where adjacent adipocytes meet. Silver stains show that adipocytes are surrounded by reticular fibers (type III collagen), which are secreted by the adipocytes. Special stains also reveal the presence of unmyelinated nerve fibers and numerous mast cells. The lipid mass in the adipocyte is not membrane-bounded. TEM reveals that the interface between the contained lipid and surrounding cytoplasm of the adipocyte is composed of a 5-nm-thick condensed layer of lipid reinforced by parallel vimentin filaments measuring 5 to 10 nm in diameter. This layer separates the hydrophobic contents of the lipid droplet from the hydrophilic cytoplasmic matrix.

Midstage lipoblasts

With continued development, the early lipoblasts assume an oval configuration. The most characteristic feature at this stage is an extensive concentration of vesicles and small lipid droplets around the nucleus and extending toward both poles of the cell. Glycogen particles appear at the periphery of the lipid droplets, and pinocytotic vesicles and basal lamina become more apparent.

lipoma

a benign, slow-growing fatty tumor located between the skin and the muscle layer are usually found in subcutaneous tissues in middle-aged and elderly individuals. They are characterized as well-defined, soft, and painless masses of mature adipocytes usually found in the subcutaneous fascia of the back, thorax, and proximal parts of the upper and lower limbs. Treatment of lipomas usually involves a simple surgical excision.

Transdifferentiation

a form of wound healing in which mature cells dedifferentiate and produce new cells that are then able to mature into cell types with a completely different function from the originating cells Adipocytes are able to undergo white-to-brown and brown-to-white transformation in response to the thermogenic needs of an organism Worth mentioning is the fact that mice with abundant natural or induced brown adipose tissue are resistant to obesity, whereas genetically modified mice without functional brown adipocytes are prone to obesity and type 2 diabetes. If the browning phenomenon is achieved by a physiologic genome-reprogramming mechanism, this mechanism could be used for future therapeutic strategies aimed at controlling the amount of brown adipose tissue in the body. This discovery may lead to the control of obesity and type 2 diabetes.

White adipose tissue secretes a variety of

adipokines, which include hormones, growth factors, and cytokines. The most notable member of adipokines is leptin. Leptin is involved in the regulation of energy homeostasis and is exclusively secreted by adipocytes. Leptin inhibits food intake and stimulates metabolic rate and loss of body weight. Thus, leptin fulfills the criteria for a circulating satiety factor that controls food intake when the body's store of energy is sufficient. In addition to leptin, adipose tissue secretes a variety of adipokines such as adiponectin, resistin, retinol binding protein 4 (RBP4), visfatin, apelin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factors (TNFs), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and angiotensinogen (AGE). Leptin also produces steroid hormones (testosterone, estrogens, and glucocorticoids). These enzymes can therefore influence the sex steroid profiles of obese individuals. Obesity-increased secretion of growth factors (tumor necrosis factor a [TNF-a], transforming growth factor b [TGF-b], and insulin-like growth factor 1 [IGF-1]) and cytokines (IL-6 and prostaglandins) may be linked to metabolic abnormalities and development of diabetes.

liposarcomas

cancers of adipose tissue They are typically detected in older individuals and are mainly found in the deep adipose tissues of the lower limbs, abdomen, and the shoulder area. Liposarcomas may contain both well-differentiated, mature adipocytes, and early, undifferentiated cells (Fig. F9.2.1). Tumors containing more cells in earlier stages of differentiation are more aggressive and more frequently metastasize. Typically, liposarcomas are surgically removed, but if a tumor has already metastasized, then both chemotherapy and

conventional lipoma

consists of mature white adipocytes

long-term weight regulation

controls appetite and metabolism on a continual basis (over months and years). Two major hormones influence this system, leptin and insulin, along with other hormones, including thyroid hormone, glucocorticoids, and hormones of the pituitary gland.

Short term weight regulation

controls appetite and metabolism on a daily basis. Recently, two small peptide hormones produced in the gastrointestinal tract—ghrelin, an appetite stimulant, and peptide YY (PYY), an appetite suppressant—have been linked to this system.

early lipoblasts

have an elongated configuration, multiple cytoplasmic processes, and abundant endoplasmic reticulum and Golgi apparatus. As lipoblastic differentiation begins, vesicles increase in number, with a corresponding decrease in rough-surfaced endoplasmic reticulum (rER). Small lipid inclusions appear at one pole of the cytoplasm. Pinocytotic vesicles and an external lamina also appear. Th e presence of an external lamina is a feature that further distinguishes adipocytes from proper connec- tive tissue cells.

Ghrelin

is a small, 28-amino-acid polypeptide produced by gastric epithelial cells. In addition to its appetite stimulatory role, it acts on the anterior lobe of the pituitary gland to release growth hormone. In humans, ghrelin functions through receptors located in the hypothalamus, increasing the sense of hunger.

Adipose tissue

is a specialized connective tissue that plays an important role in energy homeostasis. Individual fat cells, or adipocytes, and groups of adipocytes are found throughout loose connective tissue. Tissues in which adipocytes are the primary cell type are designated adipose tissue. Adipocytes play a key role in energy homeostasis.

Adipocytes

lipid droplets of adipocytes in the form of triglycerides. Triglycerides represent a dynamic form of energy storage that is added to when food intake is greater than energy expenditure and is tapped when energy expenditure is greater than food intake. Th e energy stored in adipocytes can be rapidly released for use at other sites in the body. ----- perform other functions in addition to their role as fat-storage containers. They also regulate energy metabolism by secreting paracrine and endocrine substances. The newly discovered secretory functions of adipocytes have shifted views on adipose tissue, which is now considered a major endocrine organ.

White adipocytes differentiate from-________ under the control of __________

mesenchymal stem cells PPARy/RXR transcription factors. Current evidence suggests that a transcription factor called peroxisome proliferator-activated receptor gamma (PPARy) in complex with the retinoid X receptor (RXR) play a critical role in adipocyte differentiation and initiation of lipid metabolism. It induces the maturation of early lipoblasts (adipoblasts) or preadipocytes into mature fat cells of white adipose tissue. Most of the PPARy target genes in adipose tissue influence lipogenic pathways and initiate the storage of triglycerides. Therefore, PPARy/RXR is regarded as the "master switch" regulator in the white adipocytes' differentiation.

The amount of an individual's adipose tissue is determined by two physiologic systems:

one associated with short- term weight regulation, the other with long-term weight regulation.

Insulin

the pancreatic hormone that regulates blood glucose levels, is also involved in regulation of adipose tissue metabolism. It enhances the conversion of glucose into the triglycerides of the lipid droplet by the adipocyte. Like leptin, insulin regulates weight by acting on brain centers in the hypothalamus. In contrast to leptin, insulin is required for the accumulation of adipose tissue. Antiobesity drug research is currently focusing on substances that can inhibit insulin and leptin signaling in the hypothalamus.

leptin (ob) gene,

which encodes a fat-specific messenger RNA (mRNA) for leptin, has given some insight into the mechanism of energy homeostasis. Unlike mutant mice, in most obese humans, levels of leptin mRNA in adipose tissue, as well as serum levels of leptin, are elevated. This was observed in all types of obesity, regardless of whether it is caused by genetic factors, hypothalamic lesions, or increased efficiency of food utilization. For unknown reasons, adipocytes in these obese individuals are resistant to leptin's action, and the administration of leptin does not reduce the amount of adipose tissue. Conversely, studies of individuals who have lost weight and those with anorexia nervosa show that leptin mRNA levels in their adipose tissue and serum levels of leptin are significantly reduced. Recent clinical findings indicate that leptin most likely protects the body against weight loss in times of food deprivation.

There are two types of adipose tissue:

white (unilocular) and brown (multilocular).