Genetic Obesity: Is the Defect in the Sympathetic Nervous System? A Review Through Developmental Studies in the Preobese Zucker Rat

Abstract

Conclusion

The chronological analysis of anomalies that emerge within the first postnatal week in fa/fa rats strongly suggests that increased lipid storage leading to obesity in Zucker rats is a consequence of a defect in energy expenditure. In the search for an unifying hypothesis that might explain the etiology of this genetic obesity, an alteration in the nervous system appears the most likely to agree with the monogenic transmittance of the syndrome. Such an alteration could cause a general defect in the peripheral organs, which are sympathetically innervated, and explain the decreased thermogenesis in BAT of fa/fa rats and in other organs like skeletal muscles (via decreased futile cycles activity; 150). It may also explain the decrease in the peripheral utilization of triglycerides and glucose, principally by skeletal muscles and BAT, which results in excess circulating levels of these substrates that could then be shunted for storage in WAT.

The hyperinsulinemia, which progressively develops in preobese rats from 10 days onward, could be explained either by an increased parasympathetic nervous system activity (8) or by a vagal sensitization of pancreatic insulin secretion to the increased levels of circulating glucose (105). This latter idea is consistent with a cause and effect dependency between a decreased sympathetic activity (possibly responsible for increasing plasma glucose levels) and the emergence of hyperinsulinemia.

Hyperphagia, the date of emergence of which cannot be separated from that of hyperinsulinemia, could be a consequence of the latter (78), and/or a defect in the hypothalamic control of food intake (1 5 1).

When hyperphagia and hyperinsulinemia develop, the anomalies in adipose tissue accretion get worse and a cascade development of new alterations develops in other organs (liver, muscles, brain, etc.). These alterations may give rise to a new dynamic metabolic and hormonal re-equilibration. As a result, anomalies present in older fa/fa rats may only be a consequence of earlier re-equilibrations and should be analyzed accordingly

The etiology of the genetic obesity syndrome of Zucker rats appears to result from a disturbance in the regulation of the sympathetic nervous system, whose main and first expression is a decreased thermogenesis. The primary genetic defect(s) of fa/fa rats probably resides in discrete regions of the hypothalamus or at a higher level of regulation, i.e., in the central nervous system.