Angiopoietin-like protein 8 (ANGPTL8) has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate lipoprotein lipase (LPL). In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-cholesterol and blocked LPL-facilitated hepatocyte VLDL-cholesterol uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.

Recent evidence indicates that sodium glucose cotransporter‐2 inhibitors (SGLT2i) significantly reduce the incidence of major adverse cardiovascular events in high risk patients. However, the specific effects of SGLT2i on the cardiovascular system remain poorly defined. This study tested the hypothesis that SGLT2i improves cardiac function during acute regional myocardial ischemia and reperfusion. Lean domestic swine (~50 kg; control (n = 6), SGLT2i (n = 5)) were randomized to receive either placebo or oral doses of canagliflozin (300 mg) 24 hours prior to and the morning of a terminal experimental procedure. Measurements were obtained in open chest, anesthetized swine at baseline, during a 30 min complete occlusion of the circumflex coronary artery, and during a 2 hour reperfusion period. Blood pressure (85 ± 6 mmHg), heart rate (78 ± 7 beats/min), coronary flow (0.40 ± 0.05 mL/min/g), and myocardial oxygen consumption (43 ± 6 μL O2/min/g) were unaffected by canagliflozin treatment at rest and were not significantly altered by ischemia/reperfusion in either group. At the onset of ischemia, SGLT2i produced a significant parallel increase in both left ventricular end diastolic (85 ± 9 mL to 129 ± 10 mL; P < 0.05) and end systolic volumes (29 ± 8 mL to 78 ± 9 mL; P < 0.01) that was manifest ~30 to 90 sec post coronary artery occlusion. Left ventricular volumes remained elevated throughout the ischemic period and returned to baseline levels following ~30 min of reperfusion. Ventricular volumes remained unchanged in control swine throughout the entire protocol. Canagliflozin‐mediated increases in end diastolic volume were directly associated with significant increases in stroke volume (P < 0.05) and stroke work (P < 0.05) relative to untreated controls swine during ischemia. SGLT2i also increased cardiac efficiency (P < 0.05), as defined by stroke work/myocardial oxygen consumption. No differences in myocardial substrate uptake of glucose (P = 0.54) or lactate (P = 0.16) were noted between groups at any experimental time point. These data support the hypothesis that SGLT2i preserves cardiac contractile function during regional myocardial ischemia via activation of a Frank‐Starling mechanism and independent of alterations in myocardial substrate selection. Attached figure illustrates control responses (black) and SGLT2i responses (red). Support or Funding Information NIH HL117620 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Amygdalar CRF has been implicated in the mediation of stress behaviors. The signal transduction pathways that regulate amygdalar CRF are not well understood. In this report, we have examined the effect of protein kinase A and C activators, dexamethasone, and interleukin 6 on CRF messenger RNA (mRNA) and CRF peptide expression in dissociated amygdalar cultures. The amygdala from E19 rat pups was dissected out bilaterally and dissociated in 0.25% trypsin for 10-15 min and plated. On day 17 in culture, CRF mRNA and peptide were measured following treatment with the following agents: forskolin, the phorbol ester-phorbol 12 myristate 13-acetate (TPA), dexamethasone, and interleukin-6 (IL6). Both forskolin and IL6, but not TPA, increased CRF mRNA in a time- and dose-dependent manner. Secretion and intracellular content of the CRF peptide also increased with both forskolin and IL6 treatment but not with TPA. Dexamethasone treatment did not alter the expression of CRF message or peptide. Transfection of the primary cultures with a rat CRF promoter-luciferase reporter construct followed by treatment with all four agents produced alterations in luciferase expression that were consistent with changes observed at the level of CRF mRNA and peptide. The results suggest that CRF regulation in the amygdala differs from that known to occur in the hypothalamus, and that elevation of IL6 levels within the central nervous system may directly act to stimulate CRF production and secretion from limbic structures such as the amygdala, to promote subsequent behavioral changes.

The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

and Friedman et al. 16 We also demonstrate that the human