Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice
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BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Molecular mechanisms of PUFA-enriched HFD include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation.
“Molecular mechanisms include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation [282].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [282]
An increase in UCP-1 protein expression and activity accounted for the promoted thermogenic capacity in PUFA-enriched HFD mice.
“An increase in UCP-1 protein expression and activity (acting as an efficient monocarboxylic FA anion flippase and regulated by GDP [283]) accounted for the promoted thermogenic capacity [282].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [282]
The PUFA-enriched HFD treatment seems to induce AMPKα phosphorylation, PPARα activation, and expression of Fgf21.
“Mechanistically, the treatment seems to induce AMPKα phosphorylation (possibly due to UCP-1 uncoupling/thermogenic activity and a decrease in ATP/AMP level), PPARα activation, and the expression of Fgf21 [282].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [282]
A long-chain PUFA-enriched HFD protects C57BL/6J mice against obesity, while an isocaloric diet strongly induces weight gain in the same mouse model.
“For instance, a long-chain PUFA (PolyUnsaturated Fatty Acids)-enriched HFD protects C57BL/6J mice against obesity, while an isocaloric diet strongly induces weight gain in the same mouse model [282].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [282]
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- Authors
- Worsch, S., Heikenwalder, M., Hauner, H., & Bader, B. L.
- Affiliations
- Technical University of Munich (DE)
- TUM Klinikum (DE)
- Corresponding author
- Bader, Bernhard L.
- Venue
- Nutrition & Metabolism
- Published
- 2018-09-26
- Volume
- 15
- Issue
- 1
- Pages
- 65-65
- ISSN
- 1743-7075 (ISSN-L)
- PMC
- PMC6158869
- OpenAlex
- W2893495375
- Cited by
- 34
- References
- 65
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 1
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nutrition & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Funders
- SW was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Research Training School GRK 1482/2. (GRK 1482/2)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- n-3 long-chain polyunsaturated fatty acids, diet-induced obesity, anti-obesogenic effects, brown adipose tissue thermogenesis, UCP1, mitochondrial biogenesis, fatty acid oxidation, de novo lipogenesis, AMPK, FGF21, PPARα, intestinal lipid metabolism, hepatic lipid metabolism, n-6/n-3 PUFA ratio, eicosapentaenoic acid, docosahexaenoic acid
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