da Cunha de Sá RDC et al. (2020), Fish oil reverses metabolic syndrome, adipocyte...

ECB-ART-48551

Physiol Rep 2020 Feb 01;84:e14380. doi: 10.14814/phy2.14380.

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Fish oil reverses metabolic syndrome, adipocyte dysfunction, and altered adipokines secretion triggered by high-fat diet-induced obesity.

da Cunha de Sá RDC , Cruz MM , de Farias TM , da Silva VS , de Jesus Simão J , Telles MM , Alonso-Vale MIC .

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The effect of fish oil (FO) treatment on high-fat (HF) diet-induced obesity and metabolic syndrome was addressed by analyzing dysfunctions in cells of different adipose depots. For this purpose, mice were initially induced to obesity for 8 weeks following a treatment with FO containing high concentration of EPA compared to DHA (5:1), for additional 8 weeks (by gavage, 3 times per week). Despite the higher fat intake, the HF group showed lower food intake but higher body weight, glucose intolerance and insulin resistance, significant dyslipidemia and increased liver, subcutaneous (inguinal-ING) and visceral (retroperitoneal-RP) adipose depots mass, accompanied by adipocyte hypertrophy and decreased cellularity in both adipose tissue depots. FO treatment reversed all these effects, as well as it improved the metabolic activities of isolated adipocytes, such as glucose uptake and lipolysis in both depots, and de novo synthesis of fatty acids in ING adipocytes. HF diet also significantly increased both the pro and anti-inflammatory cytokines expression by adipocytes, while HF + FO did not differ from control group. Collectively, these data show that the concomitant administration of FO with the HF diet is able to revert metabolic changes triggered by the diet-induced obesity, as well as to promote beneficial alterations in adipose cell activities. The main mechanism underlying all systemic effects involves direct and differential effects on ING and RP adipocytes.

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Genes referenced: fat4 LOC115919910

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	Figure 1. Food intake, energy efficiency, and body weight (BW) gain of mice fed with control (CO) or high‐fat (HF) diet and treated with fish oil (FO). In the first period, the animals received CO or HF diet. In the second period, the diets were maintained and the animals received water (CO and HF groups) or fish oil (HF + FO group) by oral gavage. Food intake (a), caloric intake (b), fat intake (c), food efficiency (d), energy efficiency (e) and BW gain (f) in the first period. Food intake (g), caloric intake (h), fat intake (i), food efficiency (j), energy efficiency (k), and BW gain (l) in the second period. Mean ± SEM (n = 10–20). p < .05, **p < .001
	Figure 2. GTT and ITT of mice fed with CO or HF diet and treated with FO. (a) GTT or glucose concentration versus time after administration of glucose. (b) incremental area under the curve from GTT. (c) ITT or glucose decay curve versus time after insulin administration. (d) glucose decrease rate for ITT (kITT). Mean ± SEM (n = 8–16). p < .05, p < .01, **p < .001 versus CO diet. #p < .05, ##p < .01 versus HF diet
	Figure 3. Adiposity, hypertrophy of adipocytes, cellularity, and mRNA levels of adipogenic markers from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. (a) relative weight (mg/g BW) of ING and RP fat depot. (b) ING and RP volume adipocytes. (c) ING and RP cellularity. mRNA levels of PPAR‐γ (d), CEBP‐α (e) and perilipin (f) in ING and RP adipocytes. 36B4 was used as the housekeeping gene. Mean ± SEM (n = 10–19). p < .05, p < .01, **p < .001
	Figure 4. Metabolic activities in isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. Basal 2DG‐glucose uptake (a), oleate incorporation into TAG (b), acetate incorporation into TAG (c), basal lipolysis (d) and isoproterenol (e) stimulated lipolysis by ING and RP adipocytes. Mean ± SEM (n = 8–15). p < .05, p < .01, **p < .001
	Figure 5. mRNA levels and secretion of cytokines expressed by isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. mRNA levels of TNF‐α (a), IL‐6 (b), resistin (c), MCP‐1 (d), IL‐10 (e), adiponectin (f) and leptin (g) in ING and RP adipocytes. 36B4 was used as the housekeeping gene. Mean ± SEM (n = 8–10). p < .05, p < .01, **p < .001
	Figure 6. Secretion of cytokines by isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. Secretion of TNF‐α (a), IL‐6 (b), resistin (c), MCP‐1 (d), IL‐10 (e), and adiponectin (f) by ING and RP isolated adipocytes. Mean ± SEM (n = 8–10). p < .05, p < .01, **p < .001

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	Figure 1. Food intake, energy efficiency, and body weight (BW) gain of mice fed with control (CO) or high‐fat (HF) diet and treated with fish oil (FO). In the first period, the animals received CO or HF diet. In the second period, the diets were maintained and the animals received water (CO and HF groups) or fish oil (HF + FO group) by oral gavage. Food intake (a), caloric intake (b), fat intake (c), food efficiency (d), energy efficiency (e) and BW gain (f) in the first period. Food intake (g), caloric intake (h), fat intake (i), food efficiency (j), energy efficiency (k), and BW gain (l) in the second period. Mean ± SEM (n = 10–20). p < .05, **p < .001
	Figure 2. GTT and ITT of mice fed with CO or HF diet and treated with FO. (a) GTT or glucose concentration versus time after administration of glucose. (b) incremental area under the curve from GTT. (c) ITT or glucose decay curve versus time after insulin administration. (d) glucose decrease rate for ITT (kITT). Mean ± SEM (n = 8–16). p < .05, p < .01, **p < .001 versus CO diet. #p < .05, ##p < .01 versus HF diet
	Figure 3. Adiposity, hypertrophy of adipocytes, cellularity, and mRNA levels of adipogenic markers from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. (a) relative weight (mg/g BW) of ING and RP fat depot. (b) ING and RP volume adipocytes. (c) ING and RP cellularity. mRNA levels of PPAR‐γ (d), CEBP‐α (e) and perilipin (f) in ING and RP adipocytes. 36B4 was used as the housekeeping gene. Mean ± SEM (n = 10–19). p < .05, p < .01, **p < .001
	Figure 4. Metabolic activities in isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. Basal 2DG‐glucose uptake (a), oleate incorporation into TAG (b), acetate incorporation into TAG (c), basal lipolysis (d) and isoproterenol (e) stimulated lipolysis by ING and RP adipocytes. Mean ± SEM (n = 8–15). p < .05, p < .01, **p < .001
	Figure 5. mRNA levels and secretion of cytokines expressed by isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. mRNA levels of TNF‐α (a), IL‐6 (b), resistin (c), MCP‐1 (d), IL‐10 (e), adiponectin (f) and leptin (g) in ING and RP adipocytes. 36B4 was used as the housekeeping gene. Mean ± SEM (n = 8–10). p < .05, p < .01, **p < .001
	Figure 6. Secretion of cytokines by isolated adipocytes from ING and RP fat depots of mice fed with CO or HF diet and treated with FO. Secretion of TNF‐α (a), IL‐6 (b), resistin (c), MCP‐1 (d), IL‐10 (e), and adiponectin (f) by ING and RP isolated adipocytes. Mean ± SEM (n = 8–10). p < .05, p < .01, **p < .001