High‐fat diet and fish oil affect adipocyte metabolism in a depot‐specific manner

It is well known that the white adipose tissue plays a central role in the control of metabolism; therefore it can be related to several disorders, such as obesity, type‐2 diabetes mellitus and metabolic syndrome, mainly by inflammation and hypertrophy. Chronic overfeeding with a high‐fat (HF) diet causes an increase in body weight and promotes fat accumulation. The omega‐3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are dietary compounds that are intensively studied as potent anti‐inflammatory products. The most important source of EPA and DHA is marine fish, and although fish oil (FO) has been shown in many studies to protect against metabolic diseases, not one has focused on adipocyte metabolism. More recently a study by de Sá et al. (2016), published in The Journal of Physiology, provided evidence to suggest that FO prevents the changes in adipocyte metabolism and adipokine secretion induced by the HF diet in a depot‐specific manner. The well‐conducted experiments, complemented by the relevant findings, make this work attractive.

First of all the authors showed that the HF‐diet‐fed mice exhibited more adipose tissue, glucose and insulin intolerance, increased fasting blood glucose and insulin levels, augmented blood cholesterol and LDL‐cholesterol concentrations, and elevated homeostatic model assessment of insulin resistance (HOMA‐IR), all of which were prevented by cotreatment with FO. This was to be expected since similar results have also been seen by other groups, as was mentioned by the authors. One difference in this study, however, when compared to previous ones, is that FO supplementation was initiated 4 weeks before the induction of obesity, which could potentiate the effects of FO on HF diet. With this in mind, it would also be interesting to have future studies comparing both approaches in order to confirm whether pre‐supplemention is indeed necessary or at least improves outcomes.

The most interesting data presented by de Sá and co‐workers come from the analysis of subcutaneous (inguinal, ING) and visceral (retroperitoneal, RP) adipocytes, showing that adipose depots behave differently upon HF diet. Although greater weights of adipose depots accompanied by hypertrophy of the adipocytes and an increased incorporation of oleate into triacylglycerol were seen in both ING and RP depots upon HF diet, the de novo synthesis of fatty acids (FAs) from acetate showed a significant reduction only in the RP depots, which was partially prevented by the supplementation with FO. In the same way, only RP adipocytes showed a higher rate of lipolysis, which was abolished by FO supplementation in both basal and stimulated conditions.

Another study observing that plasma concentrations of free FAs (FFAs), glycerol, glucose and insulin were increased in mice after a 4 h fast speculated that the increased plasma level of FFAs would result in an increased lipolysis in adipose tissues. It also revealed that the increases in mass and activity of hormone‐sensitive lipase and adipose triglyceride lipase are responsible for the increased lipolysis in adipose tissues, suggesting that this increased lipolytic action accelerates FFA efflux from the adipose tissues to the bloodstream, thereby accounting for systemic FFA elevation and, hence, insulin resistance in these mice (Zhai et al. 2010).

Interestingly, de Sá and collaborators also analysed glucose uptake as well as mRNA expression of glucose transporter type 4 (GLUT‐4) and observed no significant differences in RP adipocytes. However, in adipocytes coming from the ING depot there was a significant reduction in both glucose uptake and GLUT‐4 expression, which in both cases FO supplementation was able to prevent.

In fact, in a previous study examining the mechanism by which FFAs induce insulin resistance in human skeletal muscle, the authors investigated whether the reduced glucose transport activity observed could be the result of FFA effects on the GLUT‐4 transporter directly (i.e. alteration in GLUT‐4 trafficking, GLUT‐4 budding, GLUT‐4 fusion, GLUT‐4 activity, etc.), or if it could result from FFA‐induced alterations in upstream insulin signalling events, thus resulting in decreased GLUT‐4 translocation to the plasma membrane. They examined insulin receptor substrate 1 (IRS‐1)‐associated phosphatidylinositol (PI) 3‐kinase activity in muscle biopsy samples and found that similar elevations in plasma FFA levels abolished insulin‐stimulated IRS‐1‐associated PI 3‐kinase activity compared with a fourfold stimulation observed in the glycerol infusion studies. This work demonstrated that FFA‐induced insulin resistance, as reflected by changes in intramuscular glucose‐6‐phosphate concentration, occurred in temporal relationship with alterations in insulin‐stimulated PI 3‐kinase activity – an important component of the insulin signalling pathway leading to activation of glucose transport activity in skeletal muscle (Dresner et al. 1999).

Taking into account that the increased lipolysis observed by de Sá and co‐workers in RP depots could lead to an increase in FFA plasma levels as seen by Zhai and collaborators, it could be that the decrease in glucose uptake seen in ING depots would not only be related to a decrease in GLUT‐4 mRNA expression, but also due to a FFA‐induced modulation of the insulin signalling pathway as seen in skeletal muscle by Dresner et al.

It is known that the adipose tissue is able to secrete some types of interleukin and inflammatory cytokines in obese humans and that it could be implicated in the risk of cardiovascular disease (Ibrahim, 2010). In the present study, de Sá and collaborators showed an increase in pro‐inflammatory cytokines in adipocytes isolated from mice submitted to a high‐fat diet, and a significant reduction of these molecules in adipocytes from obese mice treated with FO supplementation. The interesting data here are again the differences seen between the cytokines expressed and secreted in adipocytes from RP and ING fat depots. Tumour necrosis factor α (TNF‐α) mRNA expression was significantly increased in RP adipocytes from HF‐fed mice, and this effect was reduced by FO supplementation. Although the mRNA of TNF‐α was not changed in ING adipocytes, its secretion was increased in these cells after HF diet and partially reduced when the diet was supplemented with FO. Moreover, HF diet also induced an increase in the secretion of interleukin‐6 (IL‐6) in RP adipocytes and, in the same way as TNF‐α, this secretion was decreased with FO supplementation.

Furthermore, the authors also showed a correlation between IL‐6 and the increase of fat cell size in both adipose tissue depots. A positive correlation for resistin and fat cell size was found in RP adipocytes and a strong inverse correlation of adiponectin and fat cell size was observed in ING adipose depots. Interestingly, the production of adiponectin was positively correlated with the ability to take up glucose in these cells. Taken together, these results demonstrated that HF diet changed the secretion pattern of pro‐inflammatory cytokines in RP adipocytes and the production of adiponectin, as well as the glucose uptake in ING depots. In addition, the authors demonstrated that FO administration changed the inflammatory response in both adipose tissue depots. Excitingly, according to other authors, there are indeed differences in inflammatory mechanisms between compartment‐specific adipose tissues. One relevant work that supports the study by de Sá and colleagues investigated the expression profile of a large set of pro‐ and anti‐inflammatory cytokines in abdominal subcutaneous adipose tissue (SAT) and in visceral adipose tissue (VAT) in severe obesity (Spoto et al. 2014). The vast majority of pro‐inflammatory genes were more expressed in SAT than in VAT, whereas just one pro‐inflammatory gene was more expressed in VAT. Therefore, the authors hypothesized that SAT contributes to the pro‐inflammatory burden of severe obesity more than VAT.

Collectively, all these results by de Sá et al. play a relevant role in metabolism studies. Even though the study itself could not explain the main inflammatory mechanism and prove which adipose tissue contributes more to the metabolic changes among the studied groups, the knowledge that FO supplementation in HF diet changes the inflammatory pattern in different adipose tissue depots could be one of the steps that will contribute in the combat against obesity and metabolic disease.

Additional information

Competing interests

None declared.

Funding

L.F.T. holds scholarships from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2013/13914‐0 and 2016/02881‐2).