Mitochondria, Obesity and Metabolic Syndrome
Obesity is a complex disease involving an excessive amount of body fat. Usually, obesity results from inherited, physiological and environmental factors, combined with diet, physical activity and exercise choices. An increase in visceral adipose tissue deposition induces chronic local and systemic inflammation, which mediates most obesity-related complications. The inflammation of the adipose tissue is characterized by the infiltration of activated M1 macrophages, leading to the production of reactive
oxygen species (ROS) and release of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and decreased secretion of adiponectin, an adipokine secreted by adipocytes, that is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity through its anti-inflammatory, anti-fibrotic, and antioxidant effects.
An excess of macronutrients in the adipose tissues stimulates them to release the aforementioned inflammatory mediators resulting in a chronic metabolic inflammatory state,
termed metaflammation. This chronic inflammation, as a risk factor, is an imbedded mechanism of developed diseases including obesity, metabolic syndrome, insulin resistance, and diabetes mellitus.
Recent publications from the laboratory of Dr. Lloyd, Luciole’s scientific co-founder, and his colleagues, have demonstrated a significant role in the prevention of obesity. Expression of huOGG1 in the mitochondria of transgenic mice fed a high fat diet prevents obesity, dyslipidemia and insulin resistance. Yellow Agouti mice, a mouse model based on a naturally occurring mutation that leads to hyperphagia and obesity, were also protected from obesity and fatty liver when fed a high fat diet. In both studies, the effect was attributed to an increased in whole body energy expenditure and an increase in mitochondrial content and function in white adipose tissue. Further studies indicate that expression of huOGG1 blunts adipogenesis (fat cell formation).
OGG1 deficient mice (Ogg1-/-) also had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. These data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation.
These studies demonstrate the importance of mitochondrial OGG1 in preventing the chronic inflammation, obesity, dyslipidemia and insulin resistance that define metabolic syndrome.