Adipose Tissue as an Endocrine Organ

Obesity is the result of an increase in adipocyte size (fat storage) and number (115, 116). Obesity can be interpreted based on our current understanding of fat biology as a pathological enlargement by fat cells and a failure to adequately proliferate and differentiate in response to excessive energy intake (117-121). In addition to surplus energy, hypertrophic fat cells are challenged by chronic inflammation and perhaps insulin resistance itself, posing considerable stress to its various organelles. Among these, recently the role of the endoplasmic reticulum (ER) has been highlighted as a vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance (121). Under normal conditions, the ER physiologically adapts to meet the demands related to protein and triglyceride synthesis in the differentiated fat cell, but when nutrients are in pathological excess, this overwhelms the ER activating the unfolded protein response (UPR) and triggering the development of insulin resistance through a host of mechanisms, including c-jun N-terminal kinase (JNK) activation, inflammation, and oxidative stress.

However, it was not until relatively recently that our perception of adipose tissue shifted from a rather "passive" fuel storage depot to a highly complex endocrine organ with an important role in causing systemic inflammation in obesity-related states. Because this topic has been the subjects of a number of recent in-depth reviews (66, 83, 120-122), we will consider just briefly a few aspects of the link between abnormal fat cells and inflammation. Adipocytes develop from preadipocytes present in adipose tissue and their main mission has classically been restricted to the regulation of triglyceride storage and overall body energy metabolism by the secretion of hormones such as leptin. The observation by Hotaqmisligil et al. (123) and Feinstein et al. (124) that the fat-derived proinflammatory cytokine TNF-a could induce insulin resistance was a radical departure from the classical view of adipose tissue. While the role of TNF-a to induce insulin resistance in humans with T2DM remains controversial, nevertheless the realization that adipocytes were actively involved in the secretion of many inflammatory cytokines previously believed to be secreted only by macrophages - or simply unknown - opened a new horizon in the understanding of insulin resistance, obesity and T2DM [i.e., TNF-a. IL-6, resistin, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibi-tor-1 (PAI-1), visfatin, angiotensinogen, retinol-binding protein-4 (RBP-4), and serum amyloid A (SAA)]. In a general sense, adipocytokines such as TNF-a and IL-6 are viewed as mediating insulin resistance either through promoting serine phosphorylation of key insulin signaling steps (i.e., IRS-1 mediated by TNF-a or IL-6-induced IKKp and JNK1 pathways) in liver and muscle or by infiltrating macrophages near adipose tissue cells that release cytokines and promote adipose tissue insulin resistance and the increased lipolysis that drives ectopic fat deposition in ectopic tissues. Another important observation was that 30-59% of the genes in adipocytes from obese subjects had a gene expression pattern closely related to macrophage biology (125). Note that macrophages derive from a different cell lineage than adipocytes (bone marrow stem cells), but during nutritional excess triglyceride-loaded adipocytes produce a number of cytokines that are also typical of fat-loaded activated macrophages in the arterial plaque (foam cells) . 120) . A high output of adipocytokines characterizes insulin-resistant fat cells, closing the loop by activating inflammatory pathways (i.e., NF-kP) and inducing insulin resistance in target tissues. How obesity may alter gene expression and induce similarities among adipocytes and macrophages is unknown, but could be mediated by PPARy activation (115, 122, 125), an effect that has received extensive attention in recent times. This has been of particular interest in T2DM as PPARy agonists have proven to have multiple beneficial effects on fat cell biology. Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols (TAGs) and ceramides has been recently reported to be increased in subjects with increased hepatic fat content compared to equally obese subjects with normal liver fat content (126) . Lower plasma adiponectin levels in fatty liver disease (NAFLD), as well as in obesity and T2DM, may explain these differences and point toward dysfunctional adipocyte function in these pathological states . 127), being increased by PPARy activation by thiazolidiendiones. Moreover, ob/ob mice overexpressing adiponectin are completely rescued from the diabetic phenotype at the expense of morbid obesity, offering an interesting paradox of how fat cells that can adapt successfully and store pathological amounts of fat while remaining insulin sensitive and free of diabetes (128).

Dieting Dilemma and Skinny Solutions

Dieting Dilemma and Skinny Solutions

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