Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology

Abstract

Objective: The metabolic syndrome refers to a constellation of signs including abdominal obesity, elevated serum triglycerides, low HDL-cholesterol, elevated blood pressure, and insulin resistance. Today approximately one third of the adult population has the metabolic syndrome. While there is little doubt that the signs constituting the metabolic syndrome frequently cluster, much controversy exists over the definition, pathogenesis, or clinical utility.

Design and methods: Here we present evidence from the field of comparative physiology that the metabolic syndrome is similar to the biological process that animals engage to store fat in preparation for periods of food shortage.

Results: We propose that the metabolic syndrome be changed to fat storage condition to more clearly align with its etiology. Obesity in humans is likely the consequences of both genetic predisposition (driven in part by thrifty genes) and environment. Recent studies suggest that the loss of the uricase gene may be one factor that predisposes humans to obesity today.

Conclusion: Understanding the process animals engage to switch from a lean insulin-sensitive to an obese insulin-resistant state may provide novel insights into the cause of obesity and diabetes in humans, and unique opportunities for reversing their pathology.

Figure 1. The Metabolic Syndrome as a Disorder of Fat Storage

Many animals develop features consistent with metabolic syndrome as part of the normal physiological processes involved in fat storage (shown as dotted lines). This suggests that metabolic syndrome may represent a form of fat storage. However, most animals undergo a period of fasting that brings the animal back to their regular weight, whereas many humans will progressively increase their fat stores until they become frankly obese or diabetic (solid lines).

Figure 2. Parallel Mutations in Uricase occurred During the Evolution of Hominoids in the Miocene

Adapted from Johnson RJ et al with permission of Elsevier.

Figure 3. The Thrifty Gene Hypothesis and Uricase

The uricase mutation occurred during global cooling in the mid Miocene and has been postulated to have provided a survival advantage to European apes who were undergoing periodic starvation due to the loss of fruit availability in the cooler seasonal months. Specifically, the mutation amplified the effects of fructose in fruits to increase fat stores. Later the introduction of sugar led to a major increase in fructose availability and likely has a role in the epidemic rise in obesity and diabetes.