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

Abstract

BackgroundWe 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.MethodsFor 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.ResultsCompared 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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12986-018-0291-x) contains supplementary material, which is available to authorized users.

Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice

“…Browning of white to beige fat takes on a multilocular lipid droplet appearance and increases energy expenditure and metabolic activity by promoting mitochondrial biogenesis and UCP1 function [ 47 ]. Dietary supplementation with ω3 has been reported to increase BAT thermogenic capacity and oxygen consumption by upregulation of UCP1 in mitochondria [ 48 ]. Whether TQ or TQ in combination with ω3 elicits similar effects in WAT has not been fully evaluated.…”

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

“…EPA and DHA have been of scientific interest for several years due their various associated health benefits [ 31 ]. Notably, dietary EPA and DHA supplementation has been shown to increase adipose tissue lipolysis, thermogenesis, Ucp1 expression, UCP-1 protein concentration and BAT NEFA oxidation in rodents [ 18 , 19 , 20 , 21 , 22 ]. Similarly, EPA treatment has been shown to induce Ucp1 expression in cultured human pre-adipocytes [ 17 ].…”

“…Nevertheless, the present findings cannot establish whether the associations between BAT activity and circulating EPA and DHA concentrations are mechanistic or associative. Preclinical studies support a direct mechanistic role of EPA and DHA in the upregulation BAT activity in humans [ 17 , 18 , 19 , 20 , 21 , 22 ], however indirect relationships as a result of NEFA oxidation may also have value as potential biomarkers of BAT activity. Further human studies including interventions and NEFA tracers are required to fully elucidate the relationship between n-3 NEFAs and BAT activity.…”

Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases

“…As DNP derivatives or other non-specific mitochondrial uncouplers cannot be used safely in humans, an alternative approach could be to stimulate the activity of endogenous mitochondrial uncoupling/thermogenic capacity by using synthetic, natural compounds or just by changing food composition (diet-induced thermogenesis). 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]. Molecular mechanisms include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation [282].…”

“…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]. Molecular mechanisms include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation [282]. 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].…”