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

Abstract

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.

Eicosapentaenoic and Docosahexaenoic Acids Differentially Alter Gut Microbiome and Reverse High‐Fat Diet–Induced Insulin Resistance

“…DNA extraction and high‐throughput 16S rDNA sequencing were performed as described previously. [ 74 ] Briefly, DNA was extracted from cecum content samples using the MicroElute Genomic DNA Kit (D3096‐01, Omega Bio‐tek, Inc., Norcross, GA) according to the manufacturer's instructions. The total DNA was eluted in 50 μL of elution buffer and stored at −80 °C until PCR measurement (LC‐Bio Technology Co., Ltd., Hang Zhou, Zhejiang, China).…”

Essential Fatty Acids Linoleic Acid and α‐Linolenic Acid Sex‐Dependently Regulate Glucose Homeostasis in Obesity

“…Gut microbiota was analyzed using 16S rDNA sequencing as described previously . Briefly, DNA was extracted from caecal stool samples using a Micro Elute Genomic DNA Kit.…”

Dietary arachidonic acid: a Janus face actor in brain and Alzheimer’s disease?

“…The role of intestinal microbiota should be considered to reconcile the various data on dietary ARA effects on systemic chronic sub-inflammation in obesity, Bowel disease or chronic pathologies proinflammatory. For example, Zhuang et al (2017) recently showed that dietary ARA favour obesity and by acting on the hypothalamus-liver-adipocytes axis but the effect is modulated by sex and intestinal microbiota, female mice being less pejoratively affected. This result should be related to the current work on the relationship between the gut microbiota and Alzheimer's disease (for review see Jiang et al, 2017).…”