Félix-Soriano, E. (Elisa)
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- Effects of DHA-Rich n-3 Fatty Acid Supplementation and/or Resistance Training on Body Composition and Cardiometabolic Biomarkers in Overweight and Obese Post-Menopausal Women(2021) Lorente-Cebrian, S. (Silvia); Moreno-Aliaga, M. J. (María Jesús); Félix-Soriano, E. (Elisa); García-Unciti, M.S. (María Soledad); Gonzalez-Muniesa, P. (Pedro); Palacios-Samper, N. (Natalia); Cuervo, M. (Marta); Pérez-Chávez, A. (Adriana); Santos, J. (Javier); Cobo-Díez, M.J. (María José); Martínez-Gayo, A. (Alejandro); Goikoetxea-Galarza, I. (Iñaki)Resistance training (RT) and n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation have emerged as strategies to improve muscle function in older adults. Overweight/obese postmenopausal women (55-70 years) were randomly allocated to one of four experimental groups, receiving placebo (olive oil) or docosahexaenoic acid (DHA)-rich n-3 PUFA supplementation alone or in combination with a supervised RT-program for 16 weeks. At baseline and at end of the trial, body composition, anthropometrical measures, blood pressure and serum glucose and lipid biomarkers were analyzed. Oral glucose tolerance tests (OGTT) and strength tests were also performed. All groups exhibit a similar moderate reduction in body weight and fat mass, but the RT-groups maintained bone mineral content, increased upper limbs lean mass, decreased lower limbs fat mass, and increased muscle strength and quality compared to untrained-groups. The RT-program also improved glucose tolerance (lowering the OGTT incremental area under the curve). The DHA-rich supplementation lowered diastolic blood pressure and circulating triglycerides and increased muscle quality in lower limbs. In conclusion, 16-week RT-program improved segmented body composition, bone mineral content, and glucose tolerance, while the DHA-rich supplement had beneficial effects on cardiovascular health markers in overweight/obese postmenopausal women. No synergistic effects were observed for DHA supplementation and RT-program combination.
- Effects of DHA supplementation and physical exercise on adipose tissue and metabolic health: studies in aged obese female mice and postmenopausal women(Universidad de Navarra, 2021-07-08) Félix-Soriano, E. (Elisa); Moreno-Aliaga, M. J. (María Jesús)Adipose tissue is a dynamic organ that contributes to maintain whole-body metabolic status. Three major types of adipose tissue/cells, white, brown, and beige, can be found. All of them become dysfunctional in obesity and in aging, with brown and beige showing a declined activity. Importantly, both obesity and aging are associated to a chronic, low-grade inflammation that underlies the adipose tissue dysfunction and the development of the associated comorbidities. In this context, aging obese women represent a target population for preventive strategies, since aging and obesity-pathophysiological processes are accelerated due to menopause. In this background, docosahexaenoic acid (DHA), probably through its derived specialized proresolving lipid mediators (SPMs), as well as exercise training, via its beneficial effects in several metabolic organs, could be therapeutic approaches for aging and obesity. Hence, we hypothesized that DHA supplementation and/or exercise training could ameliorate adipose tissue dysfunction in aged obese female mice, and in postmenopausal women with overweight/obesity, also reducing biomarkers of metabolic disturbances. With this aim, the first experimental study was based on long-term DHA dietary supplementation or exercise training, conducted in diet-induced obese mice from adulthood up to 18 months of age, to study the effects on subcutaneous white adipose tissue (scWAT) and interscapular brown adipose tissue (iBAT). Thereafter, a randomized clinical trial was conducted in postmenopausal women with overweight/obesity, to explore the effects of DHA supplementation and/or resistance training (RT), on body composition and metabolic biomarkers, as well as in the systemic-adipose inflammatory axis. The animal studies revealed actions for DHA on improving scWAT metabolic and inflammatory status (Chapter 1), including a reduction in adipocytes size, the downregulation of lipogenic and inflammatory genes, the upregulation of antiinflammatory M2 macrophages, and the induction of beige adipocyte genes. On iBAT, obesity and aging induced a reduction in SPMs content, which could contribute to its proinflammatory status and reduced thermogenic function (Chapter 2). The DHA-enriched diet increased UCP1 levels and n-3 PUFA derived SPMs in iBAT, without recovering its impaired response to cold. Concerning the effects of long-term exercise in obese aged mice (Chapter 3), the scWAT showed an increase in fatty acid oxidation and a reduction in inflammatory genes, lower macrophage infiltration, and an increment in thermogenic and beige adipocytes genes. However, the iBAT was less responsive to exercise, revealing only a moderate stimulation of thermogenic genes/proteins. Importantly, the effects on scWAT and iBAT could contribute to the observed systemic effects exerted by DHA, which reduced total and LDL-cholesterol, and of exercise, which improved insulin resistance and glucose tolerance. Finally, the clinical trial in postmenopausal women with overweight/obesity (Chapters 4, 5), revealed that DHA supplementation induced lower diastolic blood pressure, inflammatory platelet-to-lymphocyte ratio, and circulating triglycerides. On the other hand, RT induced local fat mass losses and muscle mass gains, maintained whole-body bone mineral content and improved glucose tolerance and scWAT ADIPONECTIN expression. Both interventions reduced circulating C-reactive protein and scWAT mRNA levels of adipocytokines (LEPTIN, CHEMERIN, IL6) and M1 macrophages markers (CD11c). The combination of both treatments did not have any relevant synergistic effect. Overall, this research provides evidence that DHA supplementation and exercise training induce a beneficial remodeling of adipose tissue that could contribute to prevent the systemic inflammation and comorbidities of obesity and aging.
- Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice(Wiley, 2021) Collantes, M. (María); Moreno-Aliaga, M. J. (María Jesús); Gil-Iturbe, E. (Eva); Dalli, J. (Jesmond); Félix-Soriano, E. (Elisa); Fernandez-Galilea, M. (Marta); Castilla-Madrigal, R. M. (Rosa María); Sainz, N. (Neira); Ly, L. (Lucy)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 DHA-derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice.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 obese-aged mice included LXB4, 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.
- Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice(Elsevier, 2023) Martinez, J.A. (José Alfredo); Villarroya, F. (Francesc); Escoté-Miró, X. (Xavier); Quesada-López, T. (Tania); Laiglesia-González, L.M. (Laura María); Lorente-Cebrian, S. (Silvia); Collantes, M. (María); Moreno-Aliaga, M. J. (María Jesús); Dalli, J. (Jesmond); Arbones-Mainar, J.M. (José M.); Félix-Soriano, E. (Elisa); Rodriguez-Ortigosa, C.M. (Carlos M.); Santamaría, E. (Eva); Martínez-Fernández, L. (Leyre); Fernandez-Galilea, M. (Marta); Vázquez, S. (Sergio); Herrero, L. (Laura); Valverde, A.M. (Ángela M.); Sainz, N. (Neira); Colón-Mesa, I. (Ignacio)Objective: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6 / ) mice. Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6 / mice. Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.
- Chronic docosahexaenoic acid supplementation improves metabolic plasticity in subcutaneous adipose tissue of aged obese female mice(Elsevier, 2023) Celay, J. (Jon); Moreno-Aliaga, M. J. (María Jesús); Gil-Iturbe, E. (Eva); Martinez-Climent, J.A. (José Ángel); Félix-Soriano, E. (Elisa); Fernandez-Galilea, M. (Marta); Sainz, N. (Neira)This study aimed to characterize the potential beneficial effects of chronic docosahexaenoic acid (DHA) supplementation on restoring subcutaneous white adipose tissue (scWAT) plasticity in obese aged female mice. Two-month-old female C57BL/6J mice received a control (CT) or a high fat diet (HFD) for 4 months. Then, 6-month-old diet-induced obese (DIO) mice were distributed into the DIO and the DIOMEG group (fed with a DHA-enriched HFD) up to 18 months. In scWAT, the DHA-enriched diet reduced the mean adipocyte size and reversed the upregulation of lipogenic genes induced by the HFD, reaching values even lower than those observed in CT animals. DIO mice exhibited an up-regulation of lipolytic and fatty oxidation gene expressions that was reversed in DHA-supplemented mice except for Cpt1a mRNA levels, which were higher in DIOMEG as compared to CT mice. DHA restored the increase of proinflammatory genes observed in scWAT of DIO mice. While no changes were observed in total macrophage F4/80+/CD11b+ content, the DHA treatment switched scWAT macrophages profile by reducing the M1 marker Cd11c and increasing the M2 marker CD206. These events occurred alongside with a stimulation of beige adipocyte specific genes, the restoration of UCP1 and pAKT/AKT ratio, and a recovery of the HFD-induced Fgf21 upregulation. In summary, DHA supplementation induced a metabolic remodeling of scWAT to a healthier phenotype in aged obese mice by modulating genes controlling lipid accumulation in adipocytes, reducing the inflammatory status, and inducing beige adipocyte markers in obese aged mice.
- Intestinal permeability, gut inflammation, and gut immune system response are linked to aging-related changes in gut microbiota composition: A study in female mice(Oxford University Press, 2024) Moreno-Aliaga, M. J. (María Jesús); Félix-Soriano, E. (Elisa); Gámez-Macías, P.E. (Paola Elizabeth); Gonzalez-Muniesa, P. (Pedro); Sainz, N. (Neira); Samblas-García, M. (Miriam)Aging entails changes at the cellular level that increase the risk of various pathologies. An association between gut microbiota and age-related diseases has also been attributed. This study aims to analyze changes in fecal microbiota composition and their association with genes related to immune response, gut inflammation, and intestinal barrier impairment. Fecal samples of female mice at different ages (2 months, 6 months, 12 months, and 18 months) and gene expression in colon tissue were analyzed. Results showed that the older mice group had a more diverse microbiota than the younger group. Additionally, the abundance of Cyanobacteria, Proteobacteria, Flavobacteriaceae, Bacteroides, Parabacteroides, Prevotellaceae_UCG-001, Akkermansia, and Parabacteroides goldsteinii increased with age. In contrast, there was a notable decline in Clostridiaceae, Lactobacillaceae, Monoglobaceae, Ligilactobacillus, Limosilactobacillus, Mucispirillum, and Bacteroides faecichinchillae. These bacteria imbalances were positively correlated with increased inflammation markers in the colon, including Tnf-α, Ccl2, and Ccl12, and negatively with the expression of tight junction genes (Jam2, Tjp1, and Tjp2), as well as immune response genes (Cd4, Cd72, Tlr7, Tlr12, and Lbp). In conclusion, high levels of diversity did not result in improved health in older mice; however, the imbalance in bacteria abundance that occurs with aging might contribute to immune senescence, inflammation, and leaky gut disease.