Hepatic Cyclooxygenase-2 Expression Protects Against Diet-Induced Steatosis, Obesity, and Insulin Resistance

Abstract

Accumulation evidence links obesity-induced inflammation as an important contributor to the development of insulin resistance, which plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. Cyclooxygenase (COX)-1 and -2 catalyze the first step in prostanoid biosynthesis. Because adult hepatocytes fail to induce COX-2 expression regardless of the proinflammatory stimuli used, we have evaluated whether this lack of expression under mild proinflammatory conditions might constitute a permissive condition for the onset of insulin resistance. Our results show that constitutive expression of human COX-2 (hCOX-2) in hepatocytes protects against adiposity, inflammation, and, hence, insulin resistance induced by a high-fat diet, as demonstrated by decreased hepatic steatosis, adiposity, plasmatic and hepatic triglycerides and free fatty acids, increased adiponectin-to-leptin ratio, and decreased levels of proinflammatory cytokines, together with an enhancement of insulin sensitivity and glucose tolerance. Furthermore, hCOX-2 transgenic mice exhibited increased whole-body energy expenditure due in part by induction of thermogenesis and fatty acid oxidation. The analysis of hepatic insulin signaling revealed an increase in insulin receptor-mediated Akt phosphorylation in hCOX-2 transgenic mice. In conclusion, our results point to COX-2 as a potential therapeutic target against obesity-associated metabolic dysfunction.Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. IR is the key primary defect underlying the development of type 2 diabetes and is a central component defining the metabolic syndrome. That IR is associated with a state of chronic low-grade inflammation has been demonstrated, and inflammation is assumed to contribute in a major way to its development (1). Besides the fact that IR is characterized by complex interactions between genetic determinants and nutritional factors, it is recognized that mediators synthesized from immune cells and adipocytes are involved in the regulation of insulin action (2). Insulin acts in target cells by binding to its specific receptor and activating a cascade of intracellular signaling events that are altered in inflammation-associated IR (3).Inflammation induces the expression of a variety of proteins, including prostaglandin-endoperoxide synthase-2, also known as cyclooxygenase (COX)-2, which catalyzes the first step in prostanoid biosynthesis. COX-2 is induced by a variety of stimuli such as growth factors, proinflammatory mediators, hormones, and other cellular

Response to Comment on Francés et al. Hepatic Cyclooxygenase-2 Expression Protects Against Diet-Induced Steatosis, Obesity, and Insulin Resistance. Diabetes 2015;64:1522–1531

“…These results agree with the data reported in our study (3) in which decreased expression of proinflammatory cytokines in white fat revealed protection against low-grade chronic inflammation. In addition, COX-2-dependent prostaglandin E 2 , acting via EP2/EP4 Gbg dimers, enhanced insulin signaling through Akt phosphorylation.…”

Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

“…Analysis of pathways and networks using the DAVID platform identified several candidate pathways for these miRNA target genes. Among them, the insulin signaling pathway was of interest because, in accordance with our previous results, COX-2 is implicated in protection against hepatic insulin resistance in mice on a high-fat diet (14). Only eight of these miRNAs (miR-146b, Let-7b, miR-183, miR-181a1*, miR-23b, miR-184, miR-204, and Let-7a) have target genes involved in the insulin signaling pathway, and their data were confirmed by real-time RT-PCR in liver extracts from Wt and COX-2-Tg mice.…”

“…We analyzed the enriched signaling pathways among the predicted gene targets of the miRNAs regulated by COX-2 and focused on the insulin signaling pathway based on our previous results that indicated that COX-2 reduces liver damage induced by hyperglycemia (15) and protects against adiposity, inflammation, and hepatic insulin resistance in mice challenged with a high-fat diet (14). These miRNA target genes were validated by real-time RT-PCR and presented increased expression in COX-2-Tg liver and in both CHL and NCL cells expressing COX-2.…”

“…Our previous results from studies performed in a model of transgenic mice constitutively expressing human COX-2 in hepatocytes (hCOX-2-Tg) indicate a protective role of COX-2 in a model of insulin resistance induced by a high-fat diet (HFD) (14) and in liver damage induced by hyperglycemia (15).…”

Foxc2 enhances proliferation and inhibits apoptosis through activating Akt/mTORC1 signaling pathway in mouse preadipocytes

“…Obesity is determined by the number and volume of adipocytes in adipose tissue, which not only depends on intracellular triglyceride synthesis and catabolic effi ciency, but also on the balance between cell proliferation and death, including necrosis and apoptosis (30)(31)(32)(33)(34). Cell proliferation is the result of mitosis that is regulated by the cell cycle and requires a variety of regulatory mechanisms to genes, either positively or negatively, to coordinate each other (35)(36)(37).…”