A number of lines of research indicate that fat tissue becomes actively harmful to other tissues with advancing age via forms of signaling. Much of this work is focused on the role of excess visceral fat tissue in long-term health. Visceral fat acts to increase the burden of senescent cells, which then promote inflammation throughout the body via inflammatory signaling, but fat cells can also act to directly generate pro-inflammatory signaling in other ways, such as via mimicking the signaling generated by infected cells. These are not the only mechanisms, and nor do fat cells act in isolation to cause issues in the aging body.
Researchers here produce evidence to show that fat cells mediate a problematic relationship between the gut microbiome and various the age-related cardiometabolic diseases with a strong inflammatory component, such as type 2 diabetes and atherosclerosis. With age, changes in the composition of the gut microbiome ensure that bacteria in the gut increasingly generate trimethylamine. Meanwhile other aspects of aging ensure that fat cells throughout the body increasingly express FMO3, converting that trimethylamine into trimethylamine-N-oxide (TMAO). TMAO is well established to promote inflammation, at this point a fairly well studied contribution to the inflammation of aging.
White adipose tissue (WAT) acts as an endocrine organ to maintain systemic energy and glucose homeostasis. Transcriptomic and proteomic analyses indicate that WAT is the first tissue showing functional decline in ageing. WAT is composed of diverse cell populations, including mature white adipocytes that produce bioactive adipokines to communicate and coordinate with the neighboring cells and distal metabolic tissues in control of systemic metabolism under varying nutritional and environmental conditions. Ageing alters composition and functionality as well as the interaction of the adipocytes and the WAT-resident cells.
Gut microbiota control host metabolism by generating an array of metabolites targeting to multiple metabolic tissues. Flavin-containing monooxygenase 3 (FMO3), a xenobiotic metabolizing enzyme primarily expressed in the liver, converts gut microbiota-produced trimethylamine (TMA) from its nutrient precursors (such as choline, L-carnitine, and betaine) into trimethylamine-N-oxide (TMAO) via hepatic FMO3. Early human and animal studies showed the important role of this microbiota-host axis in cardiometabolic health. In rodent models, knockdown of hepatic FMO3 using anti-sense oligonucleotides or global deletion of FMO3 improves hepatic insulin resistance, hyperlipidemia, obesity and atherosclerosis. Dietary treatment with TMAO promotes inflammation in visceral WAT (vWAT) by upregulating the expression of pro-inflammatory cytokines.
Although the liver is considered the main site for TMAO production via FMO3, we here demonstrate that adipocyte FMO3 is the contributor to the elevated TMAO level in ageing. We found that FMO3 and TMAO are abundantly expressed in mature adipocytes of WAT, and their levels are induced in humans and rodents with ageing via a p53-dependent pathway. Adipocyte-specific deletion of FMO3 protects against ageing- or obesity-induced functional decline of WAT, accompanied by improvement of glucose, lipid homeostasis and energy balance in mouse models. Adipocyte FMO3-derived TMAO acts as an autocrine and paracrine factor to trigger inflammasome activation and subsequent IL-1β production in mature adipocytes and adipose tissue-resident macrophages. Our proteomics analysis identifies numerous TMAO-binding proteins that participate in inflammatory pathways, particularly inflammasome activation. In summary, our study uncovers how aged adipocytes convert gut microbiota-derived metabolite to elicit adipose tissue dysfunction and systemic dysmetabolism in ageing.
