Adipose tissue compensates for defect of phosphatidylinositol 3′-kinase induced in liver and muscle by dietary fish oil in fed rats

Abstract

The present work aimed to study in rats whether substitution of a low level of fish oil (FO; 2.2% of calories) into a low-fat diet (6.6% of calories from fat as peanut-rape oil or control diet) 1) has a tissue-specific effect on insulin signaling pathway and 2) prevents dexamethasone-induced alteration of insulin signaling in liver, muscle, and adipose tissue. Sixteen rats were used for study of insulin signaling, and sixteen rats received an oral glucose load (3 g/kg). Eight rats/group consumed control diet or diet containing FO over 5 wk. Four rats from each group received a daily intraperitoneal injection of saline or dexamethasone (1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for the last 5 days of feeding. In liver, FO decreased phosphatidylinositol 3Ј-kinase (PI 3Ј-kinase) activity by 54% compared with control diet. A similar result was obtained in muscle. In both liver and muscle, FO clearly amplified the effect of dexamethasone. FO did not alter early steps of insulin signaling, and in muscle GLUT4 protein content remained unaltered. In adipose tissue, FO increased PI 3Ј-kinase activity by 74%, whereas dexamethasone decreased it by 65%; inhibition of PI 3Ј-kinase activity by dexamethasone was similar in rats fed FO or control diet, and GLUT4 protein content was increased by 61% by FO. Glycemic and insulinemic responses to oral glucose were not modified by FO. In conclusion, FO increased PI 3Ј-kinase activity in adipose tissue while inhibiting it in liver and muscle. The maintenance of whole body glucose homeostasis suggests an important role of adipose tissue for control of glucose homeostasis. eicosapentaenoic acid; docosahexaenoic acid; insulin resistance; polyunsaturated fatty acids INSULIN RESISTANCE is a common characteristic of type 2 diabetes, obesity, and metabolic syndrome (31), which results from genetic background and/or environmental factors (39). In patients with type 2 diabetes, liver, skeletal muscle, and adipose tissue are resistant to insulin action (8). In skeletal muscle of patients with type 2 diabetes, tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) and phosphatidylinositol (PI) 3Ј-kinase activity are markedly impaired (5), whereas expressions of IR, IRS-1, or the p85␣ subunit of PI 3Ј-kinase remain unaltered (17). Muscle GLUT4 protein is decreased and GLUT4 translocation is reduced by 90% during hyperinsulinemia (27). These alterations of insulin signaling in muscle participate in the decrease in muscle glucose transport, one of the main features of type 2 diabetes (7). In adipose tissue, basal expression of GLUT4 and IRS-1 are reduced, and upregulation of p85␣ by insulin is completely blunted (11).In rats, a high-fat diet (60% of calories from fat as safflower oil) inhibits liver and muscle PI 3Ј-kinase activity (35). In addition, muscle GLUT4 content and adipose tissue GLUT4 gene expression are reduced (35). These alterations likely explain the impairment of glucose transport in these tissues and at whole body level (33). When fish oil (FO), rich in long-chai...

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

“…This effect may have been mediated by increased insulin sensitization and/or decreased glucagon and epinephrine action in response to the reduction in cortisol during 11␤-HSD1 inhibition. Cortisol can decrease insulin receptor binding (13) and affect postreceptor insulin action (50) in part by decreasing PI3K activity (11). Cortisol has also been shown to maintain physiological glycogen phosphorylase levels (52) and increase glucagon binding to hepatocytes (15).…”

Glucocorticoids, metabolism and metabolic diseases

“…GC treatment leads to a down-regulation of IRS1 and IRS2 proteins, blunting intracellular insulin signal transduction [176]. Additionally, phosphoinositide 3 (PI3) kinase activity as well as Akt phosphorylation as markers of insulin signaling strength represent negative targets of GC action in rat adipocytes [177,178]. The inhibitory effect on post-receptor insulin signaling is then also translated into impaired glucose uptake by the glucose transporter 4 (Glut4).…”

Long-chain n-3 polyunsaturated fatty acids dissociate phosphorylation of Akt from phosphatidylinositol 3′-kinase activity in rats

“…In rats fed a high-fat diet rich in linoleic acid, insulin-induced PI 3-kinase activity is markedly depressed in liver and skeletal muscle, as well as its expression in adipose tissue (39). Moreover, in rats treated with a synthetic glucocorticoid (dexamethasone) that induces insulin resistance, PI 3-kinase activity stimulated by either insulin (32) or fed state (12) is deeply depressed in liver, muscle, and adipose tissue. Downstream to PI 3-kinase, activation of serine-threonine kinase Akt, a protein that plays a pivotal role in regulation of glucose transporter 4 (GLUT4) trafficking (42), is impaired in both muscle and adipose tissue of patients with type 2 diabetes (43).…”

“…Substitution of one-third of sunflower oil (rich in linoleic acid) by fish oil into a high-fat diet (60% of energy as fat) in rats completely prevents the decrease of PI 3-kinase activity and expression in muscle and adipose tissue, respectively (39). Recently, we demonstrated that substitution of a low amount of fish oil, 4.9% of metabolizable energy (ME), into a normolipidic diet containing 14.6% of energy as peanut-rape oil induced, in fed rats, a decrease in PI 3-kinase activity in both liver and muscle while activating it in adipose tissue (12). The increase in PI 3-kinase activity in adipose tissue could have compensated for its decrease in liver and muscle, which could explain how glucose tolerance and insulin sensitivity remained unaffected (12).…”