Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice

• Published in: Nutrition & metabolism Vol. 15; no. 1; p. 65
• Main Authors: Worsch, Stefanie, Heikenwalder, Mathias, Hauner, Hans, Bader, Bernhard L
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.09.2018; BioMed Central; BMC
• Subjects: Adipocytes; Adipose tissue; Adipose tissue (brown); AMP; AMP-activated protein kinase; Body fat; Brown adipose tissue; Diabetes; Diet; Diet therapy; Diet-induced obesity; Docosahexaenoic acid; Eicosapentaenoic acid; Energy; Energy metabolism; Fatty acids; Fatty liver; Fibroblast growth factors; Fibroblasts; Fish oils; Genes; Genetic aspects; Growth factors; Health aspects; High fat diet; Immunohistochemistry; Inflammation; Intestine; Kinases; Leukocytes (eosinophilic); Lipid metabolism; Lipids; Lipogenesis; Liver; Macrophages; Metabolic disorders; Metabolic pathways; Metabolites; Mitochondria; n-3 long-chain polyunsaturated fatty acids; n-6/n-3 PUFA ratio; Nervous system; Nutrition; Obesity; Oils & fats; Oxidation; Physiological aspects; Polyunsaturated fatty acids; Proteins; Respiration; Systematic review; Thermogenesis; Transcription; Unsaturated fatty acids; Energy metabolism; Diet-induced obesity; Thermogenesis; n-3 long-chain polyunsaturated fatty acids; n-6/n-3 PUFA ratio; Fibroblast growth factor 21 (FGF21); High-fat diet; Brown adipose tissue; ß-oxidation; Futile cycling
• ISSN: 1743-7075; 1743-7075
• DOI: 10.1186/s12986-018-0291-x

We previously reported on the anti-obesogenic and anti-inflammatory effects associated with n-3 long-chain polyunsaturated fatty acids (LCPUFA) in our diet-induced obesity (DIO) mouse model. Two isocaloric high-fat diets (HFDs; 48 kJ% fat), HFD (HF) and n-3 LCPUFA-enriched HFD (HF/n-3), and a control diet (C; 13 kJ% fat) were used. The underlying mechanisms however have largely remained unclear. Here, we assessed whether the reduced fat mass reflected n-3 LCPUFA-induced expression changes in lipid metabolism of the intestine, liver, and interscapular brown adipose tissue (iBAT), as well as increased iBAT thermogenic capacity. For HF/n-3, saturated and monounsaturated fatty acids were partially substituted by n-3 LCPUFA eicosapentaenoic acid and docosahexaenoic acid to achieve a balanced n-6/n-3 PUFA ratio (0.84) compared to the unbalanced ratios of HF (13.5) and C (9.85). Intestine, liver and iBAT from male C57BL/6 J mice, fed defined soybean/palm oil-based diets for 12 weeks, were further analysed. Gene and protein expression analyses, immunohistochemistry and correlation analyses for metabolic interactions were performed. Compared to HF and C, our analyses suggest significantly diminished de novo lipogenesis (DNL) and/or increased hepatic and intestinal fatty acid oxidation (ω-oxidation and peroxisomal β-oxidation) in HF/n-3 mice. For iBAT, the thermogenic potential was enhanced upon HF/n-3 consistent with upregulated expression for uncoupling protein-1 and genes involved in mitochondrial biogenesis. In addition, a higher capacity for the supply and oxidation of fatty acids was observed and expression and correlation analyses indicated a coordinated regulation of energy metabolism and futile cycling of triacylglycerol (TAG). Moreover, HF/n-3 significantly increased the number of anti-inflammatory macrophages and eosinophils and significantly enhanced the levels of activated AMP-activated protein kinase α (AMPKα), peroxisome proliferator-activated receptor α (PPARα) and fibroblast growth factor 21 (FGF21). Our data suggest that by targeting transcriptional regulatory pathways, AMPKα, and FGF21 as potential mediators, HF/n-3 activated less efficient pathways for energy production, such as peroxisomal β-oxidation, increased ATP consumption upon the induction of futile cycling of TAG, and additionally increased the thermogenic and oxidative potential of iBAT. Therefore, we consider n-3 LCPUFA as the potent inducer for upregulating energy dissipating metabolic pathways conveying anti-obesogenic effects in mice.