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Understanding the Pathophysiology of Obesity

Obesity is a chronic complex multifactorial disease consisting of exaggerated adiposity or accumulation of excess body fat that can cause major ill effects on health. Obesity occurs when a person has a body mass index (BMI) greater than or equal to 30. Obesity has a multifactorial etiology that includes genetic, environmental, socioeconomic, and behavioral or psychological influences. It is one of the most important causative factors in the pathophysiology of diabetes mellitus, insulin resistance, dyslipidemia, hypertension and atherosclerosis owing to its secretion of excessive adipokines. 

Pathophysiology: 

Dysregulation of Lipid and Glucose Metabolism: Lipotoxicity and Insulin Resistance in Obesity 

Excess stored fat is required for survival during nutritionally deprived states such as starvation. If excess fat storage is prolonged, however efficient the fat storage is, it results in obesity. Studies have reported that the storage of fatty acid as triacylglycerol within adipocytes protects against fatty acid toxicity or else, free fatty acids would circulate freely in the vasculature and produce oxidative stress by disseminating throughout the body. However, this eventually leads to the release of excessive fatty acids from enhanced lipolysis, which is stimulated by the enhanced sympathetic state existing in obesity. The release of these excessive free fatty acids then incites lipotoxicity, as lipids and their metabolites create oxidant stress to the endoplasmic reticulum and mitochondria. This affects adipose as well as non-adipose tissues, accounting for its pathophysiology in many organs, such as the liver and pancreas, and in the metabolic syndrome. The free fatty acids released from excessively stored triacylglycerol deposits also inhibit lipogenesis, preventing adequate clearance of serum triacylglycerol levels that contribute to hypertriglyceridemia. Release of free fatty acids by endothelial lipoprotein lipase from increased serum triglycerides within elevated β lipoproteins causes lipotoxicity that results in insulin-receptor dysfunction. The consequent insulin-resistant state creates hyperglycemia with compensated hepatic gluconeogenesis. The latter increases hepatic glucose production, further accentuating the hyperglycemia caused by insulin resistance. Free fatty acids also decrease utilization of insulin-stimulated muscle glucose, contributing further to hyperglycemia. Lipotoxicity from excessive free fatty acids also decreases secretion of pancreatic β-cell insulin, which eventually results in β-cell exhaustion. 

Role of Adipocyte Inflammatory Secretagogues (Adipocytokines), Including Effects of Hypertension, Macrophage, and Immune Functions

Sites and Function of Adipokines 

Adipocytes, consisting of over one billion cells, not only store triacylglycerol in fat depots in various body sites to provide energy reserves, but in aggregate constitute the largest endocrine tissue that constantly communicates with other tissues by adipocyte-released secretagogues, such as the proteohormones lectin, adiponectin, and visfatin. Along with insulin, these proteohormones help regulate body-fat mass. Visceral fat depots release inflammatory adipokines, which, along with free fatty acids, provide the pathophysiologic basis for comorbid conditions associated with obesity such as insulin resistance and diabetes mellitus type 2. Visceral adipokines are transported by the portal vascular system to the liver, enhancing nonalcoholic steatohepatitis (NASH), and also by the systemic circulation to other diverse sites. Along with fatty-acid lipotoxicity, visceral adipokines also contribute to the adipokine inflammatory injury that leads to pancreatic β-cell dysfunction, which, in turn, decreases insulin synthesis and secretion. 

Role of Specific Adipokines 

Dyslipidemia, hypertension, and atherogenesis are comorbid conditions, in addition to insulin resistance, that are associated with obesity and adversely influenced by the secretion of diverse inflammatory adipokines, particularly from white adipose tissues (WAT) in visceral fat depots. Specific adipokines enhance endothelial vasomotor tone by secreting renin, angiotensinogen, and angiotensin II, which are similar to those within the renal renin-angiotensin system (RAS), but when secreted from adipocytes, enhance hypertension in obese patients. TNF-α secretion increases in proportion to increased total body-fat mass and enhances inflammation in fatty livers and fat depots elsewhere, particularly in pancreas, mesentery, and gut visceral sites. The acute-phase reactants are important inflammatory markers that are also upregulated in the insulin-resistant state associated with diabetes mellitus type 2 and Non-alcoholic steatohepatitis (NASH). Adipocytes also stimulate fat-associated macrophages that also secrete monocyte chemoattractant protein 1 (MCP-1), macrophage migration inhibiting factor (MMIF), and resistin, all of which decrease insulin sensitivity (ie, enhance insulin resistance). 

These macrophages contribute to the enhanced inflammatory state and, as immune stimulators, enhance the mitogenactivated protein kinase family (C-Jun N-terminal Kinase, inhibitor of nuclear factor kappa beta [NF-KB] Kinase b, and phosphatidylinositol 3-Kinase), inducing the transcription factor NF-KB that allows dephosphorylation of the IRS-1 and -2 docking proteins. The latter inhibits the GLUT4 transporter of glucose, resulting in insulin resistance. 

The progressive proinflammatory state resulting from increased obesity that promotes insulin resistance also perpetuates atherogenesis throughout its development, from early endothelial fatty streaks to late-plaque formation, rupture, and thrombosis. Endothelial modulators-such as vasoactive endothelial growth factor, plasminogen activator inhibitor-angiotensinogen, renin, and angiotensin II- are secreted by white fat cells that contribute to vasomotor dysfunction and cause hypertension and endothelial injury. This process is followed by the formation of foam cells following the enhanced endothelial uptake of oxidized low density lipoproteins, free fatty acids, and other lipid metabolites that accumulate as a result of fatty acid peroxidation- all of which originate from dyslipidemic β-lipoproteins. Both endothelial and adipose cell lipoprotein lipase activity are also decreased by inflammatory cytokines such as IL-6, so that by inhibiting lipolysis they increase serum triacylglycerol levels accentuating hyper-triglyceridemia. As atherosclerosis progresses with macrophage and smooth-muscle cell infiltration, there is additional secretion of other cytokines, such as MCP-1, MMIF, and endothelin-1,that enhance the evolving inflammatory lesions of atherosclerotic plaques within the vascular wall. Other adipokine procoagulants include plasminogen activator inhibitor-1, IL-6, tumor growth factor-β, and TNF-α, which cause thrombosis, particularly from ruptured atherosclerotic plaques. Progression of atherosclerosis with plaque formation and remodeling of collagen results from the action of matrix metalloproteinases also secreted by adipocytes. This activity causes atheroma cap thinning and plaque rupture that precipitates release of the tissue factor, also promoting intravascular thrombosis. Adipokines also enhance angiogenesis and promote adipogenesis by neovascularization enhancement of WAT. 

Anti-inflammatory Secretagogues 

To counter these injurious inflammatory secretagogues, adipose cells also secrete anti-inflammatory hormones, such as adiponectin, visfatin, and the complement-related acylation-stimulating protein, which exert beneficial effects inhibiting inflammatory adipokines. In this way, protective hormones and complement proteins become both anti-inflammatory and anti-atherogenetic in action, as they concomitantly enhance insulin sensitivity and improve vascular endothelium dysfunction. This effect is most obvious when these anti-inflammatory adipokines become deficient, as when adiponectin levels decrease with increasing obesity. It is possible that adiponectin receptor deficiency, inflammatory adipokines, as well as excessive fatty acids, all contribute to insulin resistance and other comorbidities of obesity- including hypertension, dyslipidemia, and atherosclerosis- as obesity is the common cause of these disorders. Interestingly, leptin may act as both an anti-inflammatory and pro-inflammatory secretagogue, in that it enhances insulin sensitivity for glucose uptake in muscle but promotes inflammation and angiogenesis at other sites. 

Conclusion:- 

Multiple organ systems maintain metabolic homeostasis. Adipose tissue and muscles are a few of them. Adipocytes secrete hormones/chemicals known as adipokines which act on multiple cells or organs to regulate metabolism. Having a better understanding of the pathophysiology of obesity is important to all the health professionals involved in curbing obesity. To manage and prevent obesity requires an inter-professional healthcare team such as physicians, nurses, nutritionists, dieticians, and exercise physiologists to educate patients regarding diet and exercise as a lifestyle change for better patient health outcomes. 

Author

Dr. Shilpa Subramanian

Dr. Shilpa Subramanian, BDS, MDS- Qualified Periodontist with over 8 years of experience in treating complex dental problems of patients. Also managing Global  Pharmacovigilance Operations at Indegene Pvt Ltd. Passionate staying ahead of the curve in clinical and non-clinical advances in the field of pharma and healthcare.

 

References: 

1) Khanna D, Rehman A. Pathophysiology of obesity. 

2) Gastroenterol Hepatol (N Y). 2007 Nov; 3(11): 856–863. 

 

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