The brain modulates insulin sensitivity in multiple tissues

Insulin sensitivity is determined by direct effects of circulating insulin on metabolically active tissues in combination with indirect effects of circulating insulin, i.e. via the central nervous system. The dose-response effects of insulin differ between the various physiological effects of insulin. At lower insulin concentrations, circulating insulin inhibits endogenous glucose production through a combination of direct and indirect effects. At higher insulin concentrations, circulating insulin also stimulates glucose uptake and fatty acid uptake in adipose tissue, again through direct and indirect effects. High-fat diet induces insulin resistance in the central nervous system, which contributes considerably to overall insulin resistance of liver and peripheral tissues. Central insulin resistance is amendable to therapeutic intervention, reflected in the central effects of topiramate and glucagon-like peptide-1 on hepatic and peripheral insulin resistance in insulin resistant mic

Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 ± 460, P < 0.01; 2.5 nmol, 1,828 ± 684, P < 0.01; 0.75 nmol, 2,322 ± 303, P < 0.05; control: 2,790 ± 222 mmol·l -1·120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 ± 14.7 vs. 39.9 ± 5.7 μmol·min-1·kg-1, P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 ± 2.8 vs. 4.4 ± 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 ± 30.8 vs. 38.8 ± 26.4 μl/h, P < 0.001) and glucose disposal (88.1 ± 13.0 vs. 45.2 ± 6.9 μmol·min -1·kg-1, P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 ± 15.5 vs. 15.8 ± 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action

Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 +/- 460, P <0.01; 2.5 nmol, 1,828 +/- 684, P <0.01; 0.75 nmol, 2,322 +/- 303, P <0.05; control: 2,790 +/- 222 mmol.l(-1).120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 +/- 14.7 vs. 39.9 +/- 5.7 micromol.min(-1).kg(-1), P <0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 +/- 2.8 vs. 4.4 +/- 2.2 ng/ml, P <0.01). Consequently, glucose infusion rate (118.6 +/- 30.8 vs. 38.8 +/- 26.4 microl/h, P <0.001) and glucose disposal (88.1 +/- 13.0 vs. 45.2 +/- 6.9 micromol.min(-1).kg(-1), P <0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 +/- 15.5 vs. 15.8 +/- 11.4% inhibition, P <0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin actio

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outflow from the hypothalamus toward target organs and thereby influence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fight hypertriglyceridemia by specifically modulating sympathetic nervous system outflow toward liver, BAT, or WA

Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice

Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a K(ATP) channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin-resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin-sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of K(ATP) channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS

GLP-1 receptor agonism affects hepatic expression of genes involved in VLDL production, lipogenesis, and lipid homeostasis.

<p><i>E3L</i> mice were fed HFD for 13 weeks. The last 4 weeks, mice were treated with either vehicle (HFD control), CNTO3649 (0.3 or 1.0 mg/kg/day) or exendin-4 (15 or 50 μg/kg/day). As a control for HFD feeding, an additional group of mice was included fed a chow diet that received vehicle (chow control). Livers were isolated from 7 h fasted mice, and mRNA was extracted from liver pieces. mRNA values of indicated genes were normalized to <i>Cyclo</i> and <i>Hprt</i> mRNA levels. Data were calculated as fold difference as compared with the HFD control group. Values are means ± SEM for at least 6 mice per group. *P<0.05, **P<0.01, ***P<0.001 compared to HFD controls.</p

GLP-1 receptor agonism reverses high fat diet-induced hepatic steatosis.

<p><i>E3L</i> mice were fed HFD for 13 weeks. The last 4 weeks, mice were treated with either vehicle (HFD control), CNTO3649 (0.3 or 1.0 mg/kg/day) or exendin-4 (15 or 50 μg/kg/day). As a control for HFD feeding, an additional group of mice was included fed a chow diet that received vehicle (chow control). Livers were isolated from 7 h fasted mice, liver pieces were homogenized, and triglycerides, cholesterol and phospholipids were determined as nmol per mg protein. Values are means ± SEM for at least 6 mice per group. <i>*</i>P<0.05, <i>**</i>P<0.01, <i>***</i>P<0.001 compared to HFD controls.</p

GLP-1 receptor agonism reduces hepatic VLDL-TG and VLDL-apoB production without affecting VLDL particle composition.

<p><i>E3L</i> mice were fed a HFD for 22 weeks. The last 4 weeks, mice were treated with either vehicle (HFD control), CNTO3649 (1.0 or 3.0 mg/kg/day) or exendin-4 (15 or 50 μg/kg/day). As a control for HFD feeding, an additional group of mice fed a chow diet was included that received vehicle (chow control). After 7 h fasting, mice were injected with Tran³⁵S label (t = −30 min) and Triton WR-1339 (t = 0 min). Blood was drawn at the indicated time points and plasma TG concentrations were determined (A, B). VLDL-TG production rate was calculated as µmol/h from the slopes of the TG-time curves of the individual mice (C). At t = 120 min, mice were exsanguinated, and VLDL was isolated by density gradient ultracentrifugation. ³⁵S-activity was determined, and VLDL-apoB production rate was calculated as dpm.h⁻¹ (D). The VLDL-TG production rate to VLDL-apoB production rate ratio was calculated as nmol/dpm (E). The content of triglycerides, cholesterol, phospholipids and protein in VLDL was determined and calculated as % of total mass (F). Values are means ± SEM for at least 6 mice per group. <i>*</i>P<0.05, <i>**</i>P<0.01, <i>***</i>P<0.001 compared to HFD controls. TG: triglycerides; TC: total cholesterol; PL: phospholipids; Pro: protein.</p