AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance.
The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that regulates appetite and fuel metabolism. We have generated AMPK beta1(-/-) mice on a C57Bl/6 background that are viable, fertile, survived greater than 2 years, and display no visible brain developmental defects. These mice have a 90% reduction in hepatic AMPK activity due to loss of the catalytic alpha subunits, with modest reductions of activity detected in the hypothalamus and white adipose tissue and no change in skeletal muscle or heart. On a low fat or an obesity-inducing high fat diet, beta1(-/-) mice had reduced food intake, reduced adiposity, and reduced total body mass. Metabolic rate, physical activity, adipose tissue lipolysis, and lipogenesis were similar to wild type littermates. The reduced appetite and body mass of beta1(-/-) mice were associated with protection from high fat diet-induced hyperinsulinemia, hepatic steatosis, and insulin resistance. We demonstrate that the loss of beta1 reduces food intake and protects against the deleterious effects of an obesity-inducing diet.
Dzamko
Nicolas
N
Department of Medicine, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
van Denderen
Bryce J W
BJ
Hevener
Andrea L
AL
Jørgensen
Sebastian Beck
SB
Honeyman
Jane
J
Galic
Sandra
S
Chen
Zhi-Ping
ZP
Watt
Matthew J
MJ
Campbell
Duncan J
DJ
Steinberg
Gregory R
GR
Kemp
Bruce E
BE
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001066:Appetite / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002245:Carbon Dioxide / Q000378:metabolism; D003624:Darkness; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005215:Fasting / Q000097:blood; D005247:Feeding Behavior / Q000187:drug effects; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D009928:Organ Specificity / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D012119:Respiration / Q000187:drug effects
D004041:Dietary Fats; D007328:Insulin; D021122:Protein Subunits; D002245:Carbon Dioxide; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D010100:Oxygen