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Obesity, the excessive accumulation of body fat, is a main defining feature of the metabolic syndrome, and overweight is often an early indication of the future severity and development of associated pathologies. There is a graded relationship between the increase in body adipose tissue content and the severity of insulin resistance, hypertension, and altered blood lipids, in addition to a number of additional disturbances in energy, nitrogen, and xenobiotic metabolism. It is widely accepted that the manifestation of the metabolic syndrome cluster of diseases stems from the continued exposure to environmental factors [mainly diet, and especially fat intake (1)] modulated by genetic factors and epigenetic upbringing (2). Abundance of triacylglycerols in the diet translates into excess fatty acid availability, which in turn limits the utilization of dietary glucose by muscle and other tissues; we are adapted to first dispose of fatty acids for energy, preserving the glucose for the brain, as in starvation mode. Insulin resistance is, therefore a direct consequence of these preestablished priorities in the use of substrates under conditions of abundance of both carbohydrate and lipid. Nonetheless, the primarily unused but readily available energy must be processed and/or disposed of somehow. This is accomplished by a number of partial solutions, including increased energy expenditure (thermogenesis, substrate cycling, and faster protein turnover), but the most immediate (and thrifty) solution is to store the excess energy as fat for eventual use under conditions of scarcity. This storage is widely distributed, including the liver, muscle, and other organs, but their overall cumulative capacity is limited. In contrast, adipose tissue’s main function is precisely such caloric storage. Consequently, the adipocyte ends up with most of the surplus energy, largely because its barriers to prevent the accumulation of excess circulating glucose are not as effective as those that have been identified in muscle. The adipocyte incorporates fatty acids from lipoproteins and also takes a significant portion of the excess circulating glucose, which is used for lipogenesis and/or lactate production. Adipose tissue accumulation of excess triacylglycerols induces adipocyte hypertrophia, as well as relative hypoxia (in part due to tissue enlargement) (3) and acidosis because of glucose conversion to lactate (4). The storage of surplus lipids in adipose tissue, however, cannot be sustained indefinitely— the tissue cannot grow to an impossible size, destabilizing the physiological systems and potentially placing survival at serious risk. One might consider massive obesity as propelling the body toward the verge of systemic physiological collapse. Because it is difficult to process a constant energy input surplus indefinitely, adipose tissue appears to react to such excess energy dumping as if it were an aggression to its integrity and function. This reaction is mainly carried out by at least three mechanisms: 1) decreasing cell metabolism, especially the entry of substrates, glucose utilization and lipogenesis, to limit the incorporation of more energy; 2) secreting of cytokine and other metabolic signals to correct hypoxia, reducing the excessive size of fat depots (including apoptosis), and dampening tissue reactivity to hormone signals (e.g. insulin) that facilitate fat deposition; and 3) increasing diapedesis to favor the massive infiltration of immune cells to fight the aggression through depression

The Defense of Adipose Tissue against Excess Substrate-Induced Hyperthrophia: Immune System Cell Infiltration and Arrested Metabolic Activity