Metabolism In Obesity Proteins


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 Metabolism In Obesity Proteins Background

Obesity and obesity related diseases are a global problem. Obesity affects 150 million people worldwide and is characterized as pandemic disease. In the United States alone, one third of the adult population and approximately 17% of children are obese. Based on current trends researchers predict that in the United States obesity cases will increase by 65 million by the year 2030. This would result in 50% of the population being obese. Increases in obesity will escalate spending on health care. This spike in health care costs will economically burden countries.

Obesity increases the risk of cardiovascular disease, certain cancers, type II diabetes (T2DM), and all-cause mortality. In North America, the European Union, China, and other countries, obesity is considered to be responsible for up to 70-90% of the adult cases of type II diabetes mellitus (T2DM). Obesity also increases the risk of certain cancers. For example, obesity has been linked to increasing breast cancer risk in many different populations of women. It may be more frugal to combat a wide range of diseases by preventing their underlying cause, obesity.

The location of the fat dictates the risk of developing disease. Obesity primarily affects white adipose tissue (WAT). WAT provides insulation, warmth, and energy for the body. In adults, there are two major types of WAT, subcutaneous (SF) and visceral (VF) fat tissue. WAT is divided into these two categories based on the WAT’s developmental origin and location. SF, or peripheral fat, lies beneath the skin and in skeletal muscle. VF is located around internal organs and is also referred to as pericardial, perigonadal, and perirenal fat. In some studies, VF is referred to as abdominal or intraabdominal fat. Abdominal or visceral obesity is characterized by greater fat mass in the abdomen. The unhealthy accumulation of fat mass is caused by an increase in the adipocyte’s size and number of adipocytes in these obese fat pads. Obesity in the wrong physiological location can have deleterious effects. However, some adipose tissue can be health promoting.

SF may have some health promoting effects. SF has been associated with lowering levels of triglycerides, glucose, and insulin in the blood. In allograft studies, SF transplantation into the VF depot reduces weight and improves insulin tolerance. In contrast to SF, increasing the VF mass in the abdominal region is detrimental to a healthy metabolism.

Visceral obesity poses a great health risk to the individual. Visceral obesity has been linked to an increased risk of death from cardiovascular disease and certain cancers. VF accumulation, even in non-obese people, increases the risk of premature death from all causes from 150 to 200%. Other diseases are also affected by visceral obesity. Visceral obesity increases the risk of T2DM. In a Chinese male population, visceral fat was positively associated with carotid atherosclerosis. Strikingly, this association was for both obese and non-obese individuals, giving further evidence that health risk is associated with visceral fat mass. Biomarkers, such as high-sensitivity C-reactive protein, increase with diabetes, obesity, insulin resistance, and atherosclerosis. Visceral fat mass is positively correlated with high-sensitivity C-reactive protein, which further establishes the link between visceral fat, diabetes, and atherosclerosis. VF produces different pro-inflammatory cytokines than SF. VF has greater secretion of the pro-inflammatory cytokines TNF-α, IL-6, and resistin. This creates a systemic and localized state of chronic low-grade inflammation that induces insulin resistance. Moreover, glucose sensitizing hormones, like adiponectin, that improve insulin sensitivity are secreted in higher levels by SF than VF. When VF is transplanted into SF, the transplant had no effect, which further illustrates the unique properties of different fat depots.

In addition to WAT, brown adipose tissue (BAT) is the other predominant type of adipose tissue. BAT is metabolically different from WAT, particularly different from harmful VF. In BAT, stored energy from nutrients (glucose and fatty acids) can be partially converted into heat in a process known as thermogenesis. This process is driven by the mitochondrial uncoupling protein 1 (UCP1). BAT has numerous UCP1 positive mitochondria that dissipate energy. UCP1 is one major factor responsible for wasting energy in the form of heat. Brown adipocytes have smaller lipid droplets than other adipocytes, which is most likely due to increased thermogenesis. BAT and skeletal muscle arise from a similar progenitor expressing myogenic factor 5 (Myf5). Neonates have notable amounts of BAT to support thermogenesis. BAT mass declines with age. In adults, only small BAT depots are located in the neck and perivascular areas. An elevated amount of BAT is associated with resistance to obesity and improved glucose sensitivity in human and mouse obesity models.

Both BAT and SF are associated with improving metabolism. WAT can also contain thermogenic adipocytes expressing Ucp1 and Ucp2. We describe these adipocytes as ‘thermocytes’ in this dissertation, while they have also been termed as ‘brown-like’, ‘beige’ or ‘brite’ adipocytes elsewhere. White thermocytes and lipogenic adipocytes in WAT appear to originate from a similar precursor; however, they express distinct gene clusters. In WAT, thermogenesis can be induced by either sympathetic nerve stimulation, prolonged cold exposure, or consumption of high-fat and spicy diets. Induction of thermogenesis in WAT can change energy homeostasis and effectively decrease obesity and insulin resistance. Notably, the increased proportion of thermogenic to lipogenic adipocytes in VF can decrease lipid accumulation in this deleterious depot. Although thermogenesis in WAT offers a unique therapeutic opportunity to decrease abdominal fat, the current methods of inducing thermogenesis in WAT are not suitable for clinical applications.