A Non-Traditional Model of the Metabolic Syndrome: The Adaptive Significance of Insulin Resistance in Fasting-Adapted Seals

Abstract

Insulin resistance in modern society is perceived as a pathological consequence of excess energy consumption and reduced physical activity. Its presence in relation to the development of cardiovascular risk factors has been termed the metabolic syndrome, which produces increased mortality and morbidity and which is rapidly increasing in human populations. Ironically, insulin resistance likely evolved to assist animals during food shortages by increasing the availability of endogenous lipid for catabolism while protecting protein from use in gluconeogenesis and eventual oxidation. Some species that incorporate fasting as a predictable component of their life history demonstrate physiological traits similar to the metabolic syndrome during prolonged fasts. One such species is the northern elephant seal (Mirounga angustirostris), which fasts from food and water for periods of up to 4 months. During this time, ∼90% of the seals metabolic demands are met through fat oxidation and circulating non-esterified fatty acids are high (0.7–3.2 mM). All life history stages of elephant seal studied to date demonstrate insulin resistance and fasting hyperglycemia as well as variations in hormones and adipocytokines that reflect the metabolic syndrome to some degree. Elephant seals demonstrate some intriguing adaptations with the potential for medical advancement; for example, ketosis is negligible despite significant and prolonged fatty acid oxidation and investigation of this feature might provide insight into the treatment of diabetic ketoacidosis. The parallels to the metabolic syndrome are likely reflected to varying degrees in other marine mammals, most of which evolved on diets high in lipid and protein content but essentially devoid of carbohydrate. Utilization of these natural models of insulin resistance may further our understanding of the pathophysiology of the metabolic syndrome in humans and better assist the development of preventative measures and therapies.

Insulin induces a shift in lipid and primary carbon metabolites in a model of fasting-induced insulin resistance

“…Consistent with the findings by others (Tsatsoulis et al 2013; Houser et al 2013; Viscarra et al 2013; Viscarra et al 2012; Friedrich 2012) we observed an increase in baseline plasma free medium- (caprate and myristate) and long-chain (oleate, vaccinate, linoleate, EPA, and palmitate) fatty acids in late-fasted seals indicating that lipolysis increased, likely as a consequence of the increased demand for energy derived from the oxidation of FFA. Our findings are corroborated by previous data demonstrating that adipose lipases (LPL and ATGL) involved in regulation of non-esterified fatty acids (NEFA) are elevated with fasting in elephant seal pups (Viscarra et al 2012).…”

High fatty acid oxidation capacity and phosphorylation control despite elevated leak and reduced respiratory capacity in northern elephant seal muscle mitochondria

“…However, the highly variable relative differences in respiratory flux between seals and humans highlights the importance of considering substrate utilization and multiple respiratory states when evaluating adaptive changes in muscle aerobic capacity. Previous studies indicate that diving mammals rely almost exclusively on lipid metabolism for muscle ATP production (Davis, 1983;Davis et al, 1991;Davis et al, 1993;Kanatous et al, 2008;Trumble et al, 2010;Trumble and Kanatous, 2012;Houser et al, 2013;Crocker et al, 2014). Consequently, it was not surprising that compared with humans, adult NES mitochondria exhibited a greater capacity to oxidize lipid versus carbohydrate substrates (Fig.…”

“…Fig. 3C), and the known reliance of NESs on lipids for energy production (Houser et al, 2013;Crocker et al, 2014), activation of UCPs or the ANT by fatty acids might be expected to drive respiratory leak in the juvenile and adult seals. However, LEAK in presence of PalM was not increased with ontogeny; rather, it decreased relative to OXPHOS capacities, resulting in higher indices of fatty acid OXPHOS coupling in mature seals compared with pups and humans.…”

Adiposity and fat metabolism during combined fasting and lactation in elephant seals

“…Modification to the hormonal regulation of glucose metabolism is likely an adaptive mechanism in NES Houser et al, 2013) and linked with facilitating lipid metabolism. A low level of insulin secretion facilitates lipolysis, and insulin resistance promotes lipid oxidation and restricts glucose uptake to glucose-dependent tissues, such as the central nervous system.…”