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Adiposity, especially visceral adiposity, is an important risk factor for the development of insulin resistance and type 2 diabetes. In addition to its role in storing energy, adipose tissue also secretes into the circulation a number of hormones and other factors that can alter the response to insulin in distant tissues, such as liver and muscle. Many of these factors are cytokines, which have been associated with the immune system.

Fat-derived hormones that can enhance insulin signaling include leptin, adiponectin, and possibly visfatin. Those impairing insulin signaling include tumor necrosis factor-α, resistin, and several of the interleukins. Obesity has also been identified as a low-grade inflammatory state. Several possible mechanisms are discussed whereby rapid growth of adipose tissue might trigger a local inflammatory response. It is suggested that this inflammatory response and associated release of cytokines may constitute the link between obesity and insulin resistance.

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopathological conditions in patients who do not consume excessive amounts of alcohol; these conditions are characterized by hepatic steatosis with or without other pathological changes observed in liver biopsy. The pathogenesis of NAFLD and its progressive form (non-alcoholic steatohepatitis [NASH]) appears to be multifactorial and is the subject of intense investigation. Increasing evidence indicates that the pathogenesis of NAFLD and NASH is hastened by a disturbance in adipokine production. Decreased serum adiponectin and increased tumor necrosis factor-α, which are characteristic of obesity, appear to contribute to the development and progression of NASH. The role of leptin in the pathogenesis of NASH remains controversial and the involvement of serum resistin is primarily documented only in animal models, which may or may not be applicable to the human form of NAFLD. Finally, other adipokines such as vaspin, visfatin, and apelin may play important roles in the pathogenesis of NASH and require further investigation.

The International Agency for Research on Cancer has classified the evidence of a causal link between adiposity and human cancer as “sufficient” for cancers of the colon, female breast (post-menopausal), endometrium, kidney (renal cell), and esophagus (adenocarcinoma). In addition to these cancers, more recent epidemiological evidence suggests that cancers of the liver and pancreas are obesity related, and that adiposity may also increase the risk for hematopoietic cancers and aggressive prostate cancer. The mechanisms by which obesity is postulated to induce or promote tumorigenesis vary by site. These include insulin resistance and resultant chronic hyperinsulinemia, increased bioavailability of steroid hormones, and localized inflammation. The role that leptin, adiponectin, and other proteins secreted by adipocytes may have in the development and progression of tumors is an active area of research.

Obesity is a major contributor to the prevalence of cardiovascular disease (CVD) in the developed world. As adipose tissue stores increase, the structure and function of the cardiovascular system changes to enable circulation requirements to be met. Adipose tissue is not simply a passive organ to store excess energy in the form of fat, but an endocrine organ that is capable of synthesizing and releasing into the bloodstream a variety of molecules that may have unfavourable impact on CVD risk. Obesity may increase risk factors for coronary artery disease and congestive heart failure through parameters such as dyslipidemia, high blood pressure, glucose intolerance, inflammatory markers, and the prothrombotic state. By favorably modifying lipids, decreasing blood pressure, and decreasing levels of glycemia, and proinflammatory cytokines, a reduction in adipose tissue may prevent the progression of atherosclerosis or the occurrence of acute coronary syndrome events in the obese high-risk population. This chapter will discuss the relationship between obesity and CVD and will explore the differences amongst locations of adipose stores and the extent of adiposity.

Obesity and asthma are both common complex traits responsible for substantial morbidity in the developed world. The consistency of the relationship between obesity and asthma, the temporal and dose-response association, and the correlation of obesity with intermediate phenotypes for asthma suggest that the obesity-asthma link is causal. With few exceptions, the existing epidemiological studies show a consistent positive association of obesity with both incidence and prevalence of asthma in children and adults, with the effect being greater in females than in males. Obesity precedes and predicts the development of asthma, not the other way around, and the effect persists after controlling for diet and physical activity. The dose-response relationship is demonstrated by the finding that the greater the obesity the greater the effect on asthma. Studies are showing improvements in asthma in subjects who lose weight. From these observations, the main research issues at present relate to the actual biological mechanisms by which obesity influences the asthma phenotype. The specific areas requiring further investigation are: direct effect of obesity on mechanical functioning of the lung; changes in the immune or inflammatory responses directly or through genetic mechanism; sex-specific influences relating to hormones; and the influence of maternal diet on fetal programming. At present, we still do not have a good understanding of the precise relationship between obesity and asthma.

The prevalence of chronic kidney disease is growing worldwide. Epidemiological data suggest there is a causal relationship with adiposity. There are also laboratory research and clinical studies showing that adiposity is involved in the development and the progression of kidney disease itself. Mechanisms include adaptation to increased body mass, activation of sympathetic nervous and renin-angiotensin systems, effects of insulin resistance, lipid overload, and release of adipokines. Kidney disease may also affect the association of adiposity with cardiovascular outcomes. In this chapter, the interactions of adiposity and kidney disease and their effects on clinical outcomes are examined.

Obesity is a risk factor for joint disease, in particular osteoarthritis, at both weight-bearing joints such as the knee, and non-weight bearing joints such as the carpometacarpal joint of the hand. Despite this, how obesity is mechanistically associated with joint disease is unclear. Both metabolic and biomechanical factors are likely to mediate the association between obesity and joint disease, although different joint tissues such as bone and cartilage are likely to differ in their response to adiposity. It may be that biomechanical factors contribute more to joint disease at weight-bearing joints such as the knee, whereas metabolic factors associated with obesity predispose joint changes at relatively non-weight bearing joints, such as those in the hand. This chapter aims to examine the evidence for a role of obesity in joint pathology using osteoarthritis as a disease paradigm.