Mixed conjugated linoleic acid sex-dependently reverses high-fat diet-induced insulin resistance via the gut-adipose axis.

Conjugated linoleic acid (CLA) may prevent the development of obesity and metabolic disorders. However, the effects of CLA on inflammation and glucose metabolism are controversial. The underlying mechanisms governing the gut microbiota and sexual dimorphisms have also not been elucidated. The present study assessed the effect of CLA on glucose and lipid metabolism in established obesity and examined the mechanism of action based on gut microbiota. Four-week-old C57BL/6J mice were fed a high-fat diet (HFD) for 10 weeks to induce obesity. The diet-induced obese (DIO) mice were fed an HFD supplemented with mixed CLA (50% cis-9, trans-11 isomer and 50% trans-10, cis-12 isomers, 0.2% wt/wt) for 15 weeks. CLA supplementation remarkably reversed body weight in both sexes. CLA favored anti-inflammatory microbiota in male mice, mediating increased short-chain fatty acids and decreased lipopolysaccharide (LPS) production, which alleviated global inflammation and improved insulin sensitivity via inhibition of the TLR4-NF-κB pathway in adipose tissue. CLA promoted the growth of hydrogen sulfide-producing Desulfovibrio and the release of LPS in female mice, which aggravated adipose inflammation and insulin resistance. Although CLA impaired glucose metabolism in females, brown adipose tissue was significantly activated with browning of white adipose tissue in both sexes, which led to enhanced energy expenditure. Fecal transplantation from CLA-treated mice to DIO mice mimicked the sex-dependent phenotype. In conclusion, CLA decreased body weight and increased energy expenditure but sex-dependently modulated insulin resistance via the gut-adipose axis.

Arachidonic acid sex-dependently affects obesity through linking gut microbiota-driven inflammation to hypothalamus-adipose-liver axis.

Unraveling the role of dietary lipids is beneficial to treat obesity and metabolic dysfunction. Nonetheless, how dietary lipids affect existing obesity remains unknown. Arachidonic acid (AA), a derivative of linoleic acid, is one of the crucial n-6 fatty acids. The aim of this study was to investigate whether AA affects obesity through associating microbiota-driven inflammation with hypothalamus-adipose-liver axis. Four-week old C57BL/6J mice were fed with a high-fat diet (HFD, 45% fat) for 10weeks to induce obesity, and then fed a HFD enriched with 10g/kg of AA or a continuous HFD in the following 15weeks. Systemic adiposity and inflammation, metabolic profiles, gut microbiota composition, short-chain fatty acids production, hypothalamic feeding regulators, browning process of adipocytes, hepatosteatosis, and insulin resistance in adipose were investigated. The results indicated that AA aggravates obesity for both genders whereas sex-dependently affects gut microbiota composition. Also, AA favors pro-inflammatory microbiota and reduces butyrate production and circulating serotonin, which augments global inflammation and triggers hypothalamic leptin resistance via microglia accumulation in male. AA exacerbates non-alcoholic steatohepatitis along with amplified inflammation through TLR4-NF-κB pathway and induces insulin resistance. Reversely, AA alleviates obesity-related disorders via rescuing anti-inflammatory and butyrate-producing microbiota, up-regulating GPR41 and GPR109A and controlling hypothalamic inflammation in female. Nevertheless, AA modifies adipocyte browning and promotes lipid mobilization for both genders. We show that AA affects obesity likely through a gut-hypothalamus-adipose-liver axis. Our findings formulate recommendations of n-6 fatty acids like AA from dietary intake for obese subjects preferably in a sexually dimorphic way.

Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies.

BACKGROUND: The intake of fish and polyunsaturated fatty acids (PUFAs) may benefit cognitive function. However, optimal intake recommendations for protection are unknown. OBJECTIVE: We systematically investigated associations between fish and PUFA intake and mild-to-severe cognitive impairment risk. DESIGN: Studies that reported risk estimates for mild cognitive impairment (MCI), cognitive decline, dementia, Alzheimer disease (AD), or Parkinson disease (PD) from fish, total PUFAs, total n-3 (ω-3) PUFAs, or at least one n-3 PUFA were included. Study characteristics and outcomes were extracted. The pooled RR was estimated with the use of a random-effects model meta-analysis. A dose-response analysis was conducted with the use of the 2-stage generalized least-squares trend program. RESULTS: We included 21 studies (181,580 participants) with 4438 cases identified during follow-up periods (2.1-21 y). A 1-serving/wk increment of dietary fish was associated with lower risks of dementia (RR: 0.95; 95% CI: 0.90, 0.99; P = 0.042, I(2) = 63.4%) and AD (RR: 0.93; 95% CI: 0.90, 0.95; P = 0.003, I(2) = 74.8%). Pooled RRs of MCI and PD were 0.71 (95% CI: 0.59, 0.82; P = 0.733, I(2) = 0%) and 0.90 (95% CI: 0.80, 0.99; P = 0.221, I(2) = 33.7%), respectively, for an 8-g/d increment of PUFA intake. As an important source of marine n-3 PUFAs, a 0.1-g/d increment of dietary docosahexaenoic acid (DHA) intake was associated with lower risks of dementia (RR: 0.86; 95% CI: 0.76, 0.96; P < 0.001, I(2) = 92.7%) and AD (RR: 0.63; 95% CI: 0.51, 0.76; P < 0.001, I(2) = 94.5%). Significant curvilinear relations between fish consumption and risk of AD and between total PUFAs and risk of MCI (both P-nonlinearity < 0.001) were observed. CONCLUSIONS: Fishery products are recommended as dietary sources and are associated with lower risk of cognitive impairment. Marine-derived DHA was associated with lower risk of dementia and AD but without a linear dose-response relation.