in the pancreas creates beta cell dysfunction; these two conditions are necessary for the development of type 2 diabetes mellitus.
Obesity
During positive caloric balance, adipocytes initially undergo hypertrophy. The body’s appropriate response to this is to trigger adipogenesis, which allows for the generation of additional fat cells. This maintains normal adipose tissue physiologic function while increasing the body’s energy stores. However, if this adipogenesis is impaired, the hypertrophied adipocytes have pathogenic potential due to the resulting adipose tissue dysfunction. This leads to a state of hypersecretion of pro-artherogenic, pro-inflammatory, and pro-diabetic adipocytokines, which is accompanied by a decreased production of adiponectin, a protein involved in the regulation of glucose levels as well as fatty acid breakdown. Therefore, obesity can cause adipose tissue dysfunction, but not all obese individuals have a loss of adipose tissue architecture and function. The dysfunction depends on the failure of adipogenesis and the ensuing hypertrophy of the cells.
Hypertrophied adipocytes tend to expand to have a diameter that is greater than the diffusion limit of oxygen. This leads to hypoxia-induced expression of transcription factors prompting angiogenic factor expression. This decreases the adiponectin promoter and PPARg activity, reducing the stability of adiponectin mRNA, and decreasing adiponectin expression. At the same time, leptin and PA-1 gene transcription is induced in adipose tissue.
Leptin is one of the most important adipose-derived hormones, regulating appetite, hunger, behavior, and metabolism. Hence, it appears that adipocytokine dysfunction is a result of cellular mechanisms responding to local hypoxia created by hypertrophied adipocytes after the failure of adipogenesis to create more fat cells for storage from the positive caloric balance. The importance of this deregulation and the pathology it causes will be elucidated throughout the rest of this article.
Hypertrophied adipocytes, as well as total body weight, correlate with the number of macrophages in the adipose tissue and this correlation becomes even stronger when the adipose tissue in discussion is visceral. This increase in macrophages in adipose tissue may be the sentinel event for much pathology. Adipocytes that are large tend to release more free fatty acids (FFAs), which bind to the toll-like receptor 4 (TLR-4) on macrophages, stimulating NF-KB activation. This leads to increased TNF-α secretion by these macrophages. TNF-α can then activate the hypertrophied adipocytes causing increased lipolysis and secretion of interleukin 6 (IL-6), intracellular adhesion molecule-1 (ICAM-1), and macrophage chemo attractant protein-1 (MCP-1). ICAM-1 and MCP-1 are signaling molecules that cause monocyte diapedesis from blood to adipose tissue, where the monocytes will differentiate into macrophages.
This signaling process between adipocytes and macrophages creates a vicious cycle that is amplified by the fact that adiponectin, which is now low, normally inhibits TLR-activated NF-KB activity. This process as a whole leads to a pro-inflammatory state. Systemic inflammation leads to increased cardiovascular risk due to the development of atherosclerosis. This is supported by the fact that people with preexisting inflammatory diseases, such as rheumatoid arthritis or lupus, have a dramatically increased risk of cardiovascular disease at a younger age and accelerated rates of atherosclerosis.
Type 2 Diabetes
When insulin resistance increases, insulin production by pancreatic beta cells also increases; however, if this adaption fails, diabetes will ensue. An environment of insulin resistance is created in a couple of ways due to adipocyte dysfunction.
As discussed above, the adipose tissue dysfunction due to failure of adipogenesis and the resulting hypertrophy produces TNF-α, IL-6, and FFA. These all induce serine phosphorylation of the insulin receptor substrate-1 and insulin receptor substrate-2. This phosphorylation reduces the insulin receptor substrates’ abilities to be phosphorylated. This inhibits the cascade that is normally signaled when insulin binds to the receptor, resulting in insulin resistance. Another mechanism of dysfunction results due to the aforementioned increase in FFA. The presence of more than normal amounts of FFA inhibits insulin sensitivity. The presence of insulin normally inhibits hormone-sensitive lipase, but with this inhibition removed due to FFA, lipolysis is uncontrolled. This mechanism is augmented since TNF-α also upregulates triglyceride hydrolysis in adipose tissue. Adiponectin also plays a role in contributing to insulin resistance. Adiponectin inhibits hepatic glucose production and increases FA oxidation. Therefore, the decrease in adiponectin due to failure of adipogenesis, leads to insulin insensitivity.
All of these factors together create an environment for insulin resistance, which aids in the development of type 2 diabetes. In most studies, low adiponectin and elevated levels of other adipocytokines, such as TNF-α and IL-6, are associated with an increased risk of diabetes. This relates not only to their effects on insulin sensitivity but also to their effects in the pancreas leading to beta cell failure.
Adipose Tissue in Vascular Disease
The dysfunction of adipocytes due to failure of adipogenesis contributes to the development of vascular disease. Leptin upregulates Na/K ATPase pumps in the renal cortex and medulla and thus creates a leptin-provoked hypertension. Additionally, leptin increases sympathetic nerve activity to the kidneys and peripheral vasculature, creating an increased heart rate and elevated blood pressure.
Dysfunctional adipocytes, in addition to the adipocytokines already mentioned, also produce angiotensinogen and angiotensin II, which are part of the renin-angiotensinogen-aldosterone system (RAS) that contributes to salt-fluid retention and vascular tone. This increase in RAS also contributes to the decrease in adiponectin. Adiponectin is solely produced by adipocytes, and low plasma levels of adiponectin are predictors of future vascular disease. This leads to an increase in systemic blood pressures due to vasoconstriction and salt retention. Angiotensin II also can act on the endothelium to induce expression of VACM-1, ICAM-1, and MCP-1, and create local inflammation. All of this together creates atheromatous and hypertensive changes.
Due to adipocyte dysfunction, PAI-1, a regulatory protein of the coagulation cascade, is also upregulated and this increases the risk of vascular disease. With this increase, there is an increase in clotting factor levels and platelet activation, in combination with a decreased rate of fibrinolysis. This results in a change in the balance between fibrinolysis and thrombosis, favoring a hypercoaguable state and the creation of microthrombi. In addition to thrombosis, an increase in PAI-1 also increases atherogenesis due to an increase in deposition of platelets and fibrous products to plaques. Additionally, the increase inhibits migration of vascular smooth muscle cells into plaques, resulting in plaques more prone to rupture.
Metabolic Syndrome
Not only do a positive caloric balance and the failure of adipogenesis lead to dysfunction, but the location of these dysfunctional cells also plays a huge role in determining the pathologic outcome. Intra-abdominal fat pads lead to an increased risk for the development of cardiovascular disease due to what is known as metabolic syndrome. Abdominal obesity, dyslipidemia, hypertension, and insulin resistance characterize metabolic syndrome. The aforesaid molecules mentioned in this article that increase due to adipocyte dysregulation have already been shown to demonstrate the ability to cause dyslipidemia, hypertension, and insulin resistance. These factors increase significantly more if they are secreted from visceral tissue.
Additionally, the adipocytokines go directly to the liver, resulting in a significant increase in inflammatory cytokines produced by the liver as well. This all creates a far greater risk for developing cardiovascular disease than any of the individual components of metabolic syndrome on their own.
Conclusion
Adipose is an active endocrine
