Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice.
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.
Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Robby
R
Zachariah Tom
Pablo M
PM
Garcia-Roves
Rasmus J O
RJ
Sjögren
Lake Q
LQ
Jiang
Maria H
MH
Holmström
Atul S
AS
Deshmukh
Elaine
E
Vieira
Alexander V
AV
Chibalin
Marie
M
Björnholm
Juleen R
JR
Zierath
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D005260:Female; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D007328:Insulin; D020738:Leptin; D005934:Glucagon; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase