Nesfatin-1 Stimulates Fatty-Acid Oxidation by Activating AMP-Activated Protein Kinase in STZ-Induced Type 2 Diabetic Mice

The antiobesity and antidiabetic effects of the β3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a β3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that β3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for β3-adrenergic agonists in nonobese diabetic subjects.

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Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

Journal of Applied Physiology ◽

10.1152/japplphysiol.00621.2004 ◽

2005 ◽

Vol 98 (4) ◽

pp. 1221-1227 ◽

Cited By ~ 7

Author(s):

D. S. Rubink ◽

W. W. Winder

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Oxidation Rates ◽

Malonyl Coa ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

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Isoproterenol stimulates 5′-AMP-activated protein kinase and fatty acid oxidation in neonatal hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00186.2010 ◽

2010 ◽

Vol 299 (4) ◽

pp. H1135-H1145 ◽

Cited By ~ 12

Author(s):

Jagdip S. Jaswal ◽

Chad R. Lund ◽

Wendy Keung ◽

Donna L. Beker ◽

Ivan M. Rebeyka ◽

...

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Energy Demand ◽

Glucose Oxidation ◽

Acid Oxidation ◽

Acetyl Coa ◽

Lactate Oxidation ◽

Major Energy Source ◽

Amp Activated Protein Kinase

Isoproterenol increases phosphorylation of LKB, 5′-AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), enzymes involved in regulating fatty acid oxidation. However, inotropic stimulation selectively increases glucose oxidation in adult hearts. In the neonatal heart, fatty acid oxidation becomes a major energy source, while glucose oxidation remains low. This study tested the hypothesis that increased energy demand imposed by isoproterenol originates from fatty acid oxidation, secondary to increased LKB, AMPK, and ACC phosphorylation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution (0.4 mM palmitate, 11 mM glucose, 0.5 mM lactate, and 100 mU/l insulin) with or without isoproterenol (300 nM). Isoproterenol increased myocardial O2 consumption (in J·g dry wt−1·min−1; 11.0 ± 1.4, n = 8 vs. 7.5 ± 0.8, n = 6, P < 0.05), and the phosphorylation of LKB (in arbitrary density units; 0.87 ± 0.09, n = 6 vs. 0.59 ± 0.08, n = 6, P < 0.05), AMPK (0.82 ± 0.08, n = 6 vs. 0.51 ± 0.06, n = 6, P < 0.05), and ACC-β (1.47 ± 0.14, n = 6 vs. 0.97 ± 0.07, n = 6, P < 0.05), with a concomitant decrease in malonyl-CoA levels (in nmol/g dry wt; 0.9 ± 0.9, n = 8 vs. 7.5 ± 1.3, n = 8, P < 0.05) and increase in palmitate oxidation (in nmol·g dry wt−1·min−1; 272 ± 45, n = 8 vs. 114 ± 9, n = 6, P < 0.05). Glucose and lactate oxidation were increased (in nmol·g dry wt−1·min−1; 253 ± 75, n = 8 vs. 63 ± 15, n = 9, P < 0.05 and 246 ± 43, n = 8 vs. 82 ± 11, n = 6, P < 0.05, respectively), independent of alterations in pyruvate dehydrogenase phosphorylation, but occurred secondary to a decrease in acetyl-CoA content and acetyl-CoA-to-free CoA ratio. As acetyl-CoA levels decrease in response to isoproterenol, despite an acceleration of the rates of palmitate and carbohydrate oxidation, these data suggest net rates of acetyl-CoA utilization exceed the net rates of acetyl-CoA generation.

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Upregulation of 5′-AMP–Activated Protein Kinase Is Responsible for the Increase in Myocardial Fatty Acid Oxidation Rates Following Birth in the Newborn Rabbit

Circulation Research ◽

10.1161/01.res.80.4.482 ◽

1997 ◽

Vol 80 (4) ◽

pp. 482-489 ◽

Cited By ~ 86

Author(s):

A-Olufemi Makinde ◽

James Gamble ◽

Gary D. Lopaschuk

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Myocardial Fatty Acid ◽

Oxidation Rates ◽

Newborn Rabbit ◽

Amp Activated Protein Kinase

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Weight Reduction and the Impaired Plasma-Derived Free Fatty Acid Oxidation in Type 2 Diabetic Subjects1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.4.7397 ◽

2001 ◽

Vol 86 (4) ◽

pp. 1638-1644

Author(s):

E. E. Blaak ◽

B. H. R. Wolffenbuttel ◽

W. H. M. Saris ◽

M. M. A. L. Pelsers ◽

A. J. M. Wagenmakers

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Fatty Acid Oxidation ◽

Weight Reduction ◽

Acid Oxidation ◽

Free Fatty Acid Oxidation ◽

Type 2 Diabetic

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AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.6.e1107 ◽

1997 ◽

Vol 273 (6) ◽

pp. E1107-E1112 ◽

Cited By ~ 226

Author(s):

G. F. Merrill ◽

E. J. Kurth ◽

D. G. Hardie ◽

W. W. Winder

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Protein Kinase ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Fold Increase ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Malonyl Coa ◽

Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 μU/ml insulin, and 10 mM glucose with or without AICAR (0.5–2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.

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