Intestinal microbiota changes are associated with the development of obesity. However, studies in humans have generated conflicting results due to high inter-individual heterogeneity in terms of diet, age, and hormonal factors, and the largely unexplored influence of gender. In this work, we aimed to identify differential gut microbiota signatures associated with obesity, as a function of gender and changes in body mass index (BMI). Differences in the bacterial community structure were analyzed by 16S sequencing in 39 men and 36 post-menopausal women, who had similar dietary background, matched by age and stratified according to the BMI. We observed that the abundance of the Bacteroides genus was lower in men than in women (P<0.001, Q = 0.002) when BMI was > 33. In fact, the abundance of this genus decreased in men with an increase in BMI (P<0.001, Q<0.001). However, in women, it remained unchanged within the different ranges of BMI. We observed a higher presence of Veillonella (84.6% vs. 47.2%; X2 test P = 0.001, Q = 0.019) and Methanobrevibacter genera (84.6% vs. 47.2%; X2 test P = 0.002, Q = 0.026) in fecal samples in men compared to women. We also observed that the abundance of Bilophila was lower in men compared to women regardless of BMI (P = 0.002, Q = 0.041). Additionally, after correcting for age and sex, 66 bacterial taxa at the genus level were found to be associated with BMI and plasma lipids. Microbiota explained at P = 0.001, 31.17% variation in BMI, 29.04% in triglycerides, 33.70% in high-density lipoproteins, 46.86% in low-density lipoproteins, and 28.55% in total cholesterol. Our results suggest that gut microbiota may differ between men and women, and that these differences may be influenced by the grade of obesity. The divergence in gut microbiota observed between men and women might have a dominant role in the definition of gender differences in the prevalence of metabolic and intestinal inflammatory diseases.

Saturated fatty acid (SFA) high-fat diets (HFDs) enhance interleukin (IL)-1β–mediated adipose inflammation and insulin resistance. However, the mechanisms by which different fatty acids regulate IL-1β and the subsequent effects on adipose tissue biology and insulin sensitivity in vivo remain elusive. We hypothesized that the replacement of SFA for monounsaturated fatty acid (MUFA) in HFDs would reduce pro-IL-1β priming in adipose tissue and attenuate insulin resistance via MUFA-driven AMPK activation. MUFA-HFD–fed mice displayed improved insulin sensitivity coincident with reduced pro-IL-1β priming, attenuated adipose IL-1β secretion, and sustained adipose AMPK activation compared with SFA-HFD–fed mice. Furthermore, MUFA-HFD–fed mice displayed hyperplastic adipose tissue, with enhanced adipogenic potential of the stromal vascular fraction and improved insulin sensitivity. In vitro, we demonstrated that the MUFA oleic acid can impede ATP-induced IL-1β secretion from lipopolysaccharide- and SFA-primed cells in an AMPK-dependent manner. Conversely, in a regression study, switching from SFA- to MUFA-HFD failed to reverse insulin resistance but improved fasting plasma insulin levels. In humans, high-SFA consumers, but not high-MUFA consumers, displayed reduced insulin sensitivity with elevated pycard-1 and caspase-1 expression in adipose tissue. These novel findings suggest that dietary MUFA can attenuate IL-1β–mediated insulin resistance and adipose dysfunction despite obesity via the preservation of AMPK activity.

Our results suggest that long-term consumption of the Med and LFHCC diets exerts a protective effect on the development of type 2 diabetes by different specific changes in the gut microbiota, increasing the abundance of the Roseburia genus and F. prausnitzii, respectively.