Interplay between FGF21 and insulin action in the liver regulates metabolism.

The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism.

Activation of prostaglandin E receptor 4 triggers secretion of gut hormone peptides GLP-1, GLP-2, and PYY.

Prostaglandins E1 and E2 are synthesized in the intestine and mediate a range of gastrointestinal functions via activation of the prostanoid E type (EP) family of receptors. We examined the potential role of EP receptors in the regulation of gut hormone secretion from L cells. Analysis of mRNA expression in mouse enteroendocrine GLUTag cells demonstrated the abundant expression of EP4 receptor, whereas expression of other EP receptors was much lower. Prostaglandin E1 and E2, nonselective agonists for all EP receptor subtypes, triggered glucagon like peptide 1 (GLP-1) secretion from GLUTag cells, as did the EP4-selective agonists CAY10580 and TCS2510. The effect of EP4 agonists on GLP-1 secretion was blocked by incubation of cells with the EP4-selective antagonist L161,982 or by down-regulating EP4 expression with specific small interfering RNA. Regulation of gut hormone secretion with EP4 agonists was further studied in mice. Administration of EP4 agonists to mice produced a significant elevation of plasma levels of GLP-1, glucagon like peptide 2 (GLP-2) and peptide YY (PYY), whereas gastric inhibitory peptide (GIP) levels were not increased. Thus, our data demonstrate that activation of the EP4 receptor in enteroendocrine L cells triggers secretion of gut hormones.

Liver TAG transiently decreases while PL n-3 and n-6 fatty acids are persistently elevated in insulin resistant mice.

Changes in fatty acid metabolism associated with insulin resistance have been described in rats and humans but have not been well characterized in the frequently used mouse model of diet-induced obesity. To analyse the early phase as well as established insulin resistance, C57BL/6 mice were placed for 1 or 16 weeks on a high fat diet (1w-HFD, 16w-HFD). Endocrine and metabolic parameters indicated that 1w-HFD mice showed a moderate but significant induction of insulin resistance while 16w-HFD mice exhibited profound obesity-associated insulin resistance and dyslipidemias. Significant alterations in fatty acid composition were observed in plasma and liver in both groups. Liver phospholipid-associated arachidonate and docosahexaenoate were increased in both 1w-HFD and 16w-HFD mice, possibly due to increased expression of the desaturases Fads1 and Fads2. Unexpectedly, SCD1 activity and gene expression in liver were decreased in the 1w-HFD group accompanied by diminished total hepatic lipid levels, while they were increased in chronically fed mice. Our data indicate that the early phase of HFD-induced insulin resistance is not associated with elevated liver lipid concentration. Furthermore, the early and persistent rise of arachidonate and docosahexaenoate indicates that insulin resistance is not due to insufficient availability (or concentrations) of polyunsaturated fatty acids as postulated previously.

Acute-phase serum amyloid A as a marker of insulin resistance in mice.

Acute-phase serum amyloid A (A-SAA) was shown recently to correlate with obesity and insulin resistance in humans. However, the mechanisms linking obesity-associated inflammation and elevated plasma A-SAA to insulin resistance are poorly understood. Using high-fat diet- (HFD-) fed mice, we found that plasma A-SAA was increased early upon HFD feeding and was tightly associated with systemic insulin resistance. Plasma A-SAA elevation was due to induction of Saa1 and Saa2 expression in liver but not in adipose tissue. In adipose tissue Saa3 was the predominant isoform and the earliest inflammatory marker induced, suggesting it is important for initiation of adipose tissue inflammation. To assess the potential impact of A-SAA on adipose tissue insulin resistance, we treated 3T3-L1 adipocytes with recombinant A-SAA. Intriguingly, physiological levels of A-SAA caused alterations in gene expression closely resembling those observed in HFD-fed mice. Proinflammatory genes (Ccl2, Saa3) were induced while genes critical for insulin sensitivity (Irs1, Adipoq, Glut4) were down-regulated. Our data identify HFD-fed mice as a suitable model to study A-SAA as a biomarker and a novel possible mediator of insulin resistance.