The Concept of CMR

Intra-abdominal Adipose Tissue: the Culprit?

Glucose/Insulin Homeostasis

Intra-abdominal Obesity and Insulin Resistance

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One of the major conditions caused by excess intra-abdominal adipose tissue is insulin resistance, defined as the inability of insulin to perform many of its major metabolic functions. Most evidence points to a cause-and-effect relationship between excess intra-abdominal fat and insulin resistance, as well as between insulin resistance and the health complications associated with intra-abdominal obesity. It is therefore important to understand how intra-abdominal obesity leads to insulin resistance.

Key studies conducted in the early 1990s clearly established that it is the intra-abdominal component of excess fat, and not total fat, that is strongly associated with impaired insulin action (8, 9). The glucose and insulin response to a glucose load was measured in men with identical amounts of total body fat and who were grouped according to whether they had low or high amounts of intra-abdominal fat (determined by computed tomography). Men with low intra-abdominal fat had a glucose and insulin response to the oral glucose challenge that was similar to that of a lean, control group of men. Men with high intra-abdominal fat had statistically greater glucose and insulin responses than men in the other two groups. These findings have since been confirmed in both men and women (Figure 3) (10, 11).

Intra-abdominal Fat Cell Hypertrophy and the Immune Response

Under conditions that favour obesity, fat cells accumulate lipids to store excess energy and expand in size, a process known as hypertrophy. For reasons that are unclear, fat cells respond differently to hypertrophy depending on where they are located. Those in the subcutaneous compartments appear to be able to store more fat without much change in their overall metabolism. In intra-abdominal fat cells, however, a “stress response” occurs when a certain degree of hypertrophy is reached (12). This stress is ill-defined but may be related to excess energy substrates present within the adipocyte (12, 13). The stress response includes the following: 1) activation of pathways (c-Jun NH2-terminal kinase (JNK) and NFkB, two master regulators of inflammation) that encourage the production of proinflammatory cytokines, 2) overproduction of reactive oxygen species (oxidative stress), and 3) production of signals for programmed cell death (apoptosis). The stress response has two major outcomes: 1) insulin resistance first develops in the adipocyte, which reduces glucose uptake and lessens inhibition of lipolysis and 2) the stressed adipocyte secretes molecules that chemically attract cells of the immune system, mainly monocytes (a type of white blood cell), that can become macrophages once within a tissue. Normally, resident macrophages protect tissues by taking up and eliminating potentially harmful cell debris and toxins. Macrophages in healthy tissues also secrete anti-inflammatory cytokines (e.g., interleukin-10 (IL-10)) and limit production of potentially dangerous molecules such as excess nitric oxide. In hypertrophic adipose tissue, however, alternate types of macrophages flourish. This encourages rather than inhibits inflammation and harms rather than protects the adipocyte, as discussed below (14).


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