Key Points
Obesity is linked with a low-grade and chronic inflammatory state contributing to the pathogenesis of insulin resistance (IR). Obesity is also linked with substantial alterations of intestinal microbiota composition and metabolic function. Manipulating gut microbiota has a therapeutic potential in IR and type 2 diabetes (T2D) prevention. In addition, diet exerts sex-dependent effects on gut microbiota via sex-diet interaction. The role of ALA and LA in the management of IR and T2D prevention appears limited. This study therefore aimed to investigate the relation between dietary intake of ALA and LA and the subsequent T2D risk among a large group of overweight/obese participants, and the effects of long-term ALA/LA treatment on glucose homeostasis, gut microbiota, inflammation and sexual dimorphisms in diet-induced obese (DIO) mice. To further investigate the possible role of ALA and LA in obesity-induced imbalance of glucose homeostasis, a 15-week intervention study was conducted in a DIO mice fed with ALA/LA enriched HFD. The current study provides evidence that long-term dietary ALA and LA may improve glucose homeostasis and prevent T2D through the modulation of gut microbiota in a sex-dependent way. In a Chinese nationwide cohort with 14 years of follow-up, intake of ALA was reversely related to the incidence of T2D in 15,100 overweight/obese Chinese people, and LA intake was inversely related to T2D risk among overweight/obese women. The results of diet intervention study on DIO mice further demonstrated that ALA and LA supplementation ameliorated IR and inflammation in male and female mice, respectively, with sex-specific alterations in gut microbiota. Thus, long-term dietary ALA and LA supplementation may have a therapeutic potential for T2D prevention for obese individuals. The results highlight a positive role of dietary ALA and LA in the glucose metabolism in overweight/obese subjects at a high risk of T2D. Dysfunctional adipose tissue and lipotoxicity contribute to the pathogenesis of IR. Adipose tissue in visceral depots has been proposed to be a major risk factor for metabolic syndrome. This study found that iWAT was reduced by ALA supplementation with decreased circulating leptin level in male mice. The study reported that ALA and LA sex-dependently reversed obesity-induced IR in DIO male and female mice, respectively. ALA and LA supplementation sex-dependently modulated gut microbiota, which might drive the inflammatory response. ALA administration reversed a series of inflammation-associated species from Paraprevotella, Parabacteroides, Clostridium XIVa, Bilophila, Mucispirillum schaedleri and Olsenella, indicating its anti-inflammatory and fat-reducing effect on DIO male mice. Overall, ALA and LA supplementation reversed inflammation-related species along with LPS production in male and female mice, respectively, which may at least partially contribute to the ameliorated systemic inflammation and IR. ALA supplementation reduced endotoxemia, down-regulated TLR4 and inflammation cytokines expression in adipose tissue, followed by enhancing Akt phosphorylation in male mice, which was also found in LA-fed female mice and thus may lead to improved insulin sensitivity. Collectively, ALA and LA may regulate insulin signaling pathways with the modulation of adipose inflammation via gut-adipose axis. In conclusion, the results show that dietary ALA and LA (for females) produce favorable effects on glucose homeostasis in established obese individuals. These effects may result from the sex-specific alterations of intestinal microbiota that relieve adipose inflammation through gut-adipose axis. The findings provide strong evidence of ALA and LA on the prevention of T2D in overweight/obese individuals in a sex-dependent way.
ABSTRACT
SCOPE: To assess the associations of dietary linoleic acid (LA) and α-linolenic acid (ALA) with type 2 diabetes (T2D) risk in a population-based cohort and further explore the mechanism of action in a high-fat-diet induced obese (DIO) mouse model. METHODS AND RESULTS: The occurrence of T2D among 15,100 healthy Chinese adults from China Health and Nutrition Survey (CHNS, 1997-2011) were followed up for a median of 14 years. The relations of ALA and LA intakes with T2D risk were modified by BMI, with significant associations restricted to obese/overweight subjects. Among them, relative risks (95% confidence intervals) comparing extreme quartiles of intakes were 0.55 (0.32-0.93) in men and 0.53 (0.34-0.85) in women for ALA, while 0.71 (0.41-1.16) in men and 0.56 (0.36-0.89) in women for LA. DIO mice were fed with LA or ALA enriched HFD (0.2% wt/wt) for 15 weeks. Significant sex-dependent changes of gut microbiota were detected in LA or ALA fed DIO mice. Endotoxemia, systematic and adipose inflammation were relieved in ALA fed male mice and LA fed female mice. CONCLUSIONS: Long-term intake of LA (for women only) and ALA may have protective effect on T2D development for obese/overweight subjects through sex-specific gut microbiota modulation and gut-adipose axis.
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