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Interactions between adipose and lymphoid tissues at the molecular, cellular, and tissue levels are summarized, with emphasis on the special composition and metabolic properties of perinodal adipose tissue that is anatomically associated with lymph nodes. Perinodal adipose tissue intervenes between the diet and nutrition of the immune system, modulating the action of dietary lipids on immune function. The roles of peptide- and lipid-derived messenger molecules are complementary; precursors of prostaglandins and leukotrienes are specific fatty acids that are often essential constituents of the diet and may be supplied to lymphoid cells by paracrine interactions with adjacent adipocytes. Prolonged stimulation of paracrine interactions may induce local hypertrophy of adipose depots associated with lymphoid structures. Specialization of adipose tissue for paracrine interactions may be a unique, advanced feature of mammals that supports faster, more efficient immune processes and permits fever and other energetically expensive defences against pathogens to take place simultaneously with immune responses and unrelated functions such as lactation and exercise. The possible roles of local interactions between adipose and other tissues, and defects thereof, in human diseases, including HIV-associated lipodystrophy, Crohn’s disease, lymphedema, atherosclerosis and in obesity and starvation, are briefly reviewed.

Recently, the endocrine activity of adipose tissue cells has been intensively studied. In effect, a wide range of exported secretory proteins, dubbed adipokines, have been identified as constituents of the adipose proteome (adipokinome). Besides their effects on glucose and energy metabolism, adipokines are potent modulators of inflammation. This chapter provides a state-of-the-science review of adipokine-mediated paracrine signaling that may be implicated in the pathogenesis of inflammation-related diseases such as atherosclerosis, thyroid-associated ophthalmopathy, and breast cancer. We also point out a possible contribution of adipose tissue-associated mast cell secretory activity to the development of these diseases. Finally, we provide arguments for yin-yang (protective vs pathogenic) roles of adipokines in inflammation. This hypothesis may provide further novel drug targets for the development of adipopharmacology of inflammatory diseases.

Bone marrow (BM) adipose tissue should no longer be considered simply as a filling material for bone cavities that is not needed for hematopoietic activity. In addition to its potential role as an energy store, BM adipose tissue exhibits a considerable adaptive plasticity and secretes a broad spectrum of hormones, cytokines and growth factors whose receptors are present on different cells of the stromal microenvironment. BM adipocytes, originating like osteoblasts from mesenchymal stem cells, display a marked metabolic and secretory activity. Among the various secreted adipokines, leptin, and adiponectin have opposite effects on hematopoiesis, immunity, inflammation, and bone remodeling. As a whole, a counterbalance exists between adipogenesis and erythropoiesis, and between adipose and bone formation. The better knowledge of the different paracrine and endocrine agents involved in the subtle and complex regulation of hematopoiesis and its osseous environment suggests that BM adipose tissue may represent a target for drugs in situations such as blood diseases or osteoporosis.

It is estimated that globally more than 1 billion adults are overweight and at least 300 million are obese. This epidemic evolved over many decades in the industrialized countries; however, today it is occurring in a little as 10 years in underdeveloped countries. In the United States, the prevalence of overweight increased significantly from 56% in 1994 to 65.2% in 1999–2000 with individuals at the higher end of the body mass index getting larger at a faster rate than the remaining population in both men and women and in all race/ethnic groups. Women in all age groups have higher obesity prevalence than men. Alarmingly, this epidemic is no longer restricted to adults. Childhood obesity has increased more than threefold in the United States in the past three decades with the majority of the increase occurring within the past 10 years. Initially, obesity in children was primarily isolated to those from lower economic households; however, recently this association has been weakening as greater numbers of middle and upper income children have become obese. Obesity is associated with many diseases and tremendously increases health care costs. Although there is consensus that this epidemic is increasing throughout the developed world, the causes for the surge remain unknown and pose challenges for clinicians, researchers and policy makers.

The dramatic increase in obesity in both children and adults over the past two to three decades represents a national and global concern because obesity can significantly increase the risk of a myriad of chronic health conditions. Macroenvironmental influences on food consumption, including changes in food supply trends, fast food consumption, increases in portion size and food availability as well as changes in physical activity patterns in schools and workplaces have been implicated. Societal efforts undertaken to stem the surge of obesity in children and adults must address this “toxic environment,” which encourages food over-consumption and discourages physical activity. Some community-based efforts aimed at reversing this trend are meeting with promising results; however, additional research, policy changes, and a committed partnership between industry, schools, indivi duals and the media may be necessary to achieve lasting impact.

This chapter reviews the developmental pathways contributing to the origin of obesity. Evolutionary considerations are emphasized. At birth more than half of a human baby’s metabolism is devoted to the brain and it is suggested that the extreme neonatal and early childhood adiposity of humans is an adaptation to provide an energy reserve during periods of nutritional stress arising from infections and the process of weaning. This chapter also reviews the substantial experimental and clinical evidence for prenatal and early postnatal factors in the development of obesity. Developmental pathways that may lead to obesity include fetal undernutrition caused by an impaired intrauterine environment, fetal overnutrition and macrosomia caused by maternal diabetes, and infant overnutrition caused by excessive early feeding. There is evidence for interactions between these pathways and for intergenerational influences. Finally, this chapter discusses the implications for the global obesity epidemic of mismatch between the genotype, environment, and lifestyle, and underlines the potential role of inappropriate adaptive responses during development in populations undergoing rapid nutritional transition.

The last 50 yr have witnessed a major epidemic of obesity in Western societies. The development of obesity has a strong genetic component, yet the timescale of its increase cannot have come about because of population genetic changes. Consequently, the most accepted model is that obesity is a consequence of a gene-environment interaction. This current model suggests that we have an ancient genetic predisposition to deposit fat that is particularly expressed in the modern environment. Why we have this genetic predisposition has been a matter of much speculation. There is currently a broad consensus that over evolutionary time we have been exposed to regular periods of extreme food shortage (famines), during which time fatter individuals would have had a selective advantage. Consequently, individuals with genes promoting the efficient deposition of fat during periods between famines (so-called “thrifty genes”) would be favored. In the modern environment this genetic predisposition prepares us for a famine that never comes, and an epidemic of obesity follows.This chapter presents five fundamental flaws with the famine hypothesis for the genetic origins of obesity. The flaws are that (1) modern hunter-gatherer and subsistence farming communities show no fat deposition between famines; (2) famines occur only about once every 100–150 yr and involve increases in total mortality that only rarely exceed 10% of the population; (3) most people in famines die of disease rather than starvation, the latter factor accounting for between 5 and 25% of the famine mortality; (4) famine is a modern phenomenon and most human populations have probably not experienced more than 100 famine events in their history; and (5) the age distribution of mortality during famine would not result in differential mortality between lean and obese people. Even ignoring this latter factor, a simple genetic model presented in this chapter shows that famines provide insufficient selective advantage over an insufficient time period for a thrifty gene to have any penetration in the modern human population.

In humans, lipodystrophies constitute a heterogeneous group of inherited or acquired disorders characterized by the selective loss of adipose tissue. There is considerable variation in the extent of adipose tissue loss and the severity of metabolic complications resulting from insulin resistance, such as hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Among genetic lipodystrophies, the fat loss is observed either since birth as in congenital generalized lipodystrophy, or it occurs later in life as in familial partial lipodystrophy. Defects in several genes such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPAR-γ), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2) have been found in patients with genetic lipodystrophies. Additional loci still remain to be discovered. Acquired lipodystrophies mainly occur due to autoimmune mediated fat loss or because of HIV-1 protease inhibitors induced adipose tissue atrophy. This chapter discusses various features of inherited and acquired lipodystrophies and their pathogenesis. We further discuss various possible mechanisms for the loss of adipose tissue based on our current understanding of adipocyte biology.

Cachexia is brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, chronic kidney disease (CKD), AIDS, cystic fibrosis, chronic heart failure, rheumatoid arthritis, and Alzheimer’s disease. Cachexia has a stronger correlation with survival than any other current measure of diseases such as AIDS, cancer, and CKD. The underlying mechanism of increased resting metabolic rate may involve the increased activity of mitochondrial uncoupling proteins. Chronic overproduction of cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, may lead to cachexia in various chronic illness models, through the nuclear factor-KB and ATP-ubiquitin-dependent proteolytic pathways. Inhibition of these cytokines in experimental models ameliorated cachexia. Cytokines may also act on the central nervous system to alter the release and function of neuropeptides and melanocortin receptors in the hypothalamus, thereby altering both appetite and metabolic rate. Further research into the molecular pathways leading to cachexia may lead to novel therapeutic therapy for this devastating and potentially fatal complication of chronic disease.

Obesity has a negative effect on the health of patients and is becoming an increasing problem worldwide. Morbid obesity in particular affects most major organ systems and is implicated in several of the most lethal medical conditions: diabetes, myocardial ischemia, hypertension, and many cancers. Weight loss has been shown to reverse many of the comorbidities associated with obesity, with a resulting positive benefit to the patient’s health and quality of life. Achieving substantial and persistent weight loss is difficult and, to date, surgery has been the only truly effective option for treatment of obesity. Obesity has effects on multiple organ systems. Whereas some effects are permanent, many can be reversed if the patient loses a substantial amount of weight. This includes the endocrine system (diabetes), the musculoskeletal system (degenerative joint disease), and the cardiovascular system (hypertension, congestive heart failure, hypercoagulability and stroke). Dieting and exercise can be effective strategies for the moderately overweight but have a high failure rate (>90%) in the morbidly obese. Medical treatments have a mixed history and, in general, have only moderate efficacy and high side effect profiles. Surgery has been shown to be the most effective long term weight-loss strategy but is a relatively high-risk endeavor in this patient population. The laparoscopic gastric bypass is currently the most widely used bariatric surgery, achieving around 75% excess weight loss at 5-yr follow-up.

Obesity has a major detrimental effect on a patient’s health. Many of the diseases and comorbidities related to obesity can be reversed or stabilized with substantial weight loss, which currently is best achieved by surgery.