Genetic Factors

Genetic factors are clearly involved in the phenomenon of central accumulation of body fat. Such factors could be present locally in the adipose tissues in question, or in the regulatory mechanisms involved in adipose tissue distribution. A major factor in this regard is probably the activity of the HPA axis, which has been shown to be strongly dependent on genetic factors (61).

A first target for examining molecular genetic factors in men with elevated central body fat has been the gene locus of the glucocorticoid receptor (GR), because the men with perturbed diurnal cortisol secretion discussed in the section on obesity often show abnormalities in the suppression of the HPA axis by dexamethasone (5). We then found that a known polymorphism of the GR gene locus, situated in the first intron, was associated with centralization of body fat as well as insulin resistance and, furthermore, an exaggerated stimulated cortisol secretion (62). Furthermore, another polymorphism in the promoter region is associated with elevated basal cortisol secretion (63). There are thus genetic markers for centralization of fat depots in this gene, probably, if functionally significant, acting via regulation of the HPA axis.

In women additional polymorphisms, localized in microsatellites of genes involved in androgen metabolism and sensitivity seem to be involved (21), as discussed in a preceding section.

Other polymorphisms of potential general interest for the syndrome of elevated central fat are those involved in the regulation of the sympathetic nervous system. Such polymorphisms have been found in the beta-2-adrenergic receptor and in the dopamine-2 receptor, both associated with elevated blood pressure. Polymorphisms of the leptin receptor are, however, apparently protective for hypertension in obesity (64-66).

These early findings demonstrate that the syndrome of central fat accumulation is associated with several gene polymorphisms, indicating a complex genetic background of the syndrome.

WHY DOES FAT ACCUMULATE PREDOMINANTLY IN CENTRAL DEPOTS?

The mechanistic, mainly endocrine background to visceral fat accumulation has been reviewed elsewhere (6). One may wonder from a teleological viewpoint why humans in a wide variety of conditions store an excess fraction of body fat in central depots.

These depots are equipped with a very sensitive fat mobilization system, which becomes even more efficient by a dense innervation and a rich blood flow to remove mobilized free fatty acids to the portal circulation, and subsequently after hepatic extraction, to systemic circulation. Accumulation of depot fat in these portally drained depots thus serves as an easily available substrate for important liver and peripheral functions in, for example, muscles. The substrate delivery to the periphery is in the form of both free fatty acids and very low density lipoprotein triglycerides, synthesized in the liver (for review see Bjorntorp (16). The accumulation of central fat is more pronounced in men than women. Specific localization of fat accumulation seems to have a clear survival value, particularly in men, who were particularly dependent on their muscles for survival in ancient times.

One may also look upon this phenomenon as a reserve depot for periods when the surrounding milieu is threatening, and where much available energy is best stored in easily mobilizable depots, and not, for example, in the gluteo-femoral depot of women, which seems to be constructed for specific child-bearing purposes (6). Such a construction is, however, outdated in current urbanized societies. When this excess is not used for purposes of energy delivery to muscles after longer stressful periods with accumulation of central fat, these depots remain intact as a sign of long-term environmental pressures, which lead to disease by mechanisms involving neuroendocrine and autonomic mechanisms, as discussed above.

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