Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice

Abstract

Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2-and 18-month-old lean (CT) female mice and in 18-month-old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)-derived LXs and DHAderived MaRs and PDs were the most abundant SPMs in BAT of young CT mice.Research (University of Navarra). JD is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z) Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obeseaged mice included LXB 4 , MaR2, 4S,14S-diHDHA, 10S,17S-diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA-derived SPMs, without modifying LXs.However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese-aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese-aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.

Changes Induced by Aging and Long-Term Exercise and/or DHA Supplementation in Muscle of Obese Female Mice

“…As described in previous studies of our group, no significant changes were observed in BW or fat mass after long-term DHA supplementation and/or physical exercise [ 39 , 40 ]. In addition, no significant differences were observed between groups regarding absolute and relative lean mass.…”

“…In this respect, we have recently reported that a 16-week resistance training (RT) program (alone or in combination with Docosahexaenoic acid (DHA)) improved the lower and upper limb muscle strength and quality in overweight/obese postmenopausal women [ 38 ]. Moreover, recent studies of our group in aged and obese mice have shown that DHA and/or treadmill training can delay the progression of non-alcoholic fatty liver disease and inflammation [ 39 ] and that long-term DHA supplementation was able to reduce inflammation in the dysfunctional brown adipose tissue (BAT), as well as the alteration in lipid metabolism biomarkers (total and LDL-cholesterol) that characterizes aging and obesity in mice [ 40 ].…”

PET/MRI-Evaluated Activation of Brown Adipose Tissue via Cold Exposure Impacts Lipid Metabolism

“…The results showed the enhancement of the expression of browning genes in subcutaneous WAT and thermogenic genes in BAT. Félix-Soriano et al [ 15 ] discovered that a high-fat diet with DHA supplementation restored UCP1 expression in BAT. Lynes et al [ 16 ] observed that the level 12,13-diHOME was elevated in the plasma of humans and mice exposed to cold.…”

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity

“…This lower activity of BAT is related to a higher susceptibility of suffering obesity and type 2 DM and an increase of BAT activity has been suggested as a possible therapeutic strategy against obesity due to its thermogenic function [ 58 , 60 ]. We have recently reported a reduced iBAT activity in aged CT mice that was aggravated in aged DIO mice [ 61 ]. The various factors contributing to the loss of BAT with age have not been yet established [ 62 ].…”