Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice
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Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice. / Zachariah Tom, Robby; Garcia-Roves, Pablo M; Sjögren, Rasmus J O; Jiang, Lake Q; Holmström, Maria H; Deshmukh, Atul S; Vieira, Elaine; Chibalin, Alexander V; Björnholm, Marie; Zierath, Juleen R.
In: Diabetes, Vol. 63, No. 5, 05.2014, p. 1560-71.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice
AU - Zachariah Tom, Robby
AU - Garcia-Roves, Pablo M
AU - Sjögren, Rasmus J O
AU - Jiang, Lake Q
AU - Holmström, Maria H
AU - Deshmukh, Atul S
AU - Vieira, Elaine
AU - Chibalin, Alexander V
AU - Björnholm, Marie
AU - Zierath, Juleen R
PY - 2014/5
Y1 - 2014/5
N2 - AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the γ3 subunit (AMPKγ3(R225Q)) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3(R225Q) (γ3(R225Q)) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKγ3(R225Q) prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3(R225Q)) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3(R225Q) mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3(R225Q) mice, but not in ob/ob-γ3(R225Q) mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3(R225Q) mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-γ3(R225Q) mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3(R225Q) are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKγ3(R225Q) mutation.
AB - AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the γ3 subunit (AMPKγ3(R225Q)) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3(R225Q) (γ3(R225Q)) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKγ3(R225Q) prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3(R225Q)) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3(R225Q) mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3(R225Q) mice, but not in ob/ob-γ3(R225Q) mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3(R225Q) mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-γ3(R225Q) mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3(R225Q) are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKγ3(R225Q) mutation.
KW - Acetyl-CoA Carboxylase/metabolism
KW - Adenylate Kinase/metabolism
KW - Animals
KW - Female
KW - Glucagon/metabolism
KW - Insulin/metabolism
KW - Insulin Resistance/physiology
KW - Leptin/genetics
KW - Lipid Metabolism
KW - Male
KW - Mice
KW - Mice, Obese
KW - Muscle, Skeletal/drug effects
KW - Obesity/metabolism
KW - Phosphorylation/drug effects
U2 - 10.2337/db13-0670
DO - 10.2337/db13-0670
M3 - Journal article
C2 - 24487023
VL - 63
SP - 1560
EP - 1571
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 5
ER -
ID: 218626868