Metabolic Syndrome and β-Oxidation of Long-Chain Fatty Acids in the Brain, Heart, and Kidney Mitochondria

Abstract

We present evidence that metabolic syndrome (MetS) represents the postreproductive stage of the human postembryonic ontogenesis. Accordingly, the genes governing this stage experience relatively weak evolutionary selection pressure, thus representing the metabolic phenotype of distant ancestors with β-oxidation of long-chain fatty acids (FAs) as the primary energy source. Mitochondria oxidize at high-rate FAs only when succinate, glutamate, or pyruvate are present. The heart and brain mitochondria work at a wide range of functional loads and possess an intrinsic inhibition of complex II to prevent oxidative stress at periods of low functional activity. Kidney mitochondria constantly work at a high rate and lack inhibition of complex II. We suggest that in people with MetS, oxidative stress is the central mechanism of the heart and brain pathologies. Oxidative stress is a secondary pathogenetic mechanism in the kidney, while the primary mechanisms are kidney hypoxia caused by persistent hyperglycemia and hypertension. Current evidence suggests that most of the nongenetic pathologies associated with MetS originate from the inconsistencies between the metabolic phenotype acquired after the transition to the postreproductive stage and excessive consumption of food rich in carbohydrates and a sedentary lifestyle.

1060 BGRS/SB-2022 Current views on the mechanisms of aging

“…Olivetty et al (1995) found that men's hearts undergo a linear loss of approximately 64 million cells from the age of 17 to 95, whereas, in women, the structural properties of the heart remained unchanged [5]. In our experiments, we have shown that long-chain fatty acids oxidize at a high rate only in the presence of supporting substrates, which are amino acids and mitochondrial metabolites pyruvate and succinate [4,6]. Studies on the gender differences in energy metabolism have shown that women consume more fatty acids (FAs) than men, whereas men, in addition to FAs, consume significant amounts of pyruvate and amino acids [7,8].…”

“…One of the critical features of aging among mammals is that females age slower and live longer [3]. Studies on human energy metabolism have shown significant gender differences, particularly in the consumption of fatty acids [reviewed in 1,4]. Olivetty et al (1995) found that men's hearts undergo a linear loss of approximately 64 million cells from the age of 17 to 95, whereas, in women, the structural properties of the heart remained unchanged [5].…”

“…Studies on the gender differences in energy metabolism have shown that women consume more fatty acids (FAs) than men, whereas men, in addition to FAs, consume significant amounts of pyruvate and amino acids [7,8]. We have suggested that before menopause, women oxidize FAs less efficiently and thus produce less ROS than men [1,4]. However, after menopause, with the development of the metabolic syndrome (MetS), women's energy metabolism becomes similar to men's, and the rate of aging accelerates [9].…”

“…Metabolic syndrome is the consequence of the transition to the porstreproductive stage of human ontogenesis. From this point of view [1,4], most external and metabolic features of MetS reflect the fact that this stage of ontogenesis is governed by the genes of our distant ancestors, at least for the people living in the Northern Hemisphere. At MetS, fatty acids become the primary energy source for all functions, which dramatically increases the production of superoxide radicals and their protonated form perhydroxyl radical (HO2 • ), which is the inducer of the isoprostane pathway of lipid peroxidation (IPLP) in mitochondria [4,10].…”

Nuclear Receptor RORα/γ: Exciting Modulators in Metabolic Syndrome and Related Disorders

“…Metabolic syndrome (MetS) is a cluster of conditions manifested as insulin resistance, obesity, fatty liver, and hyperlipidemia ( 1 ). The number of patients with MetS in the USA is more than one-third of the total population, while over 200 million Chinese adults suffer from it ( 2 ).…”