Ablation of AMP-activated protein kinase alpha2 activity exacerbates insulin resistance induced by high-fat feeding of mice.
OBJECTIVE
We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.


METHODS
Muscle-specific transgenic mice expressing an inactive form of the AMPK alpha2 catalytic subunit (alpha2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks.


RESULTS
Compared with wild-type mice, glucose tolerance in alpha2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 microU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by approximately 50% in alpha2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the alpha2i TG mice. High-fat feeding in alpha2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle.


CONCLUSIONS
The lack of skeletal muscle AMPK alpha2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK alpha2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.
Fujii
Nobuharu
N
Department of Medicine, Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Ho
Richard C
RC
Manabe
Yasuko
Y
Jessen
Niels
N
Toyoda
Taro
T
Holland
William L
WL
Summers
Scott A
SA
Hirshman
Michael F
MF
Goodyear
Laurie J
LJ
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D006003:Glycogen; D055372:AMP-Activated Protein Kinases; D005947:Glucose