Mice deficient in phosphofructokinase-M have greatly decreased fat stores.
Synthesis of triacylglycerol requires the glucose-derived glycerol component, and glucose uptake has been viewed as the rate-limiting step in glucose metabolism in adipocytes. Furthermore, adipose tissue contains all three isoforms of the glycolytic enzyme phosphofructokinase (PFK). We here report that mice deficient in the muscle isoform PFK-M have greatly reduced fat stores. Mice with disrupted activity of the PFK-M distal promoter were obtained from Lexicon Pharmaceuticals, developed from OmniBank OST#56064. Intra-abdominal fat was measured by magnetic resonance imaging of the methylene proton signal. Lipogenesis from labeled glucose was measured in isolated adipocytes. Lipolysis (glycerol and free fatty acid release) was measured in perifused adipocytes. Intra-abdominal fat in PFK-M-deficient female mice (5-10 months old) was 17 +/- 3% of that of wild-type littermates (n = 4; P < 0.02). Epididymal fat weight in 15 animals (7-9.5 months) was 34 +/- 4% of control littermate (P < 0.002), with 10-30% lower body weight. Basal and insulin-stimulated lipogenesis in PFK-M-deficient epididymal adipocytes was 40% of the rates in cells from heterozygous littermates (n = 3; P < 0.05). The rate of isoproterenol-stimulated lipolysis in wild-type adipocytes declined approximately 10% after 1 h and 50% after 2 h; in PFK-M-deficient cells it declined much more rapidly, 50% in 1 h and 90% in 2 h, and lipolytic oscillations appeared to be damped (n = 4). These results indicate an important role for PFK-M in adipose metabolism. This may be related to the ability of this isoform to generate glycolytic oscillations, because such oscillations may enhance the production of the triacylglycerol precursor alpha-glycerophosphate.
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Lisa
L
Getty-Kaushik
Jason C
JC
Viereck
Jessie M
JM
Goodman
Zifang
Z
Guo
Nathan K
NK
LeBrasseur
Ann-Marie T
AM
Richard
John N
JN
Flanagan
Gordon C
GC
Yaney
James A
JA
Hamilton
Keith
K
Tornheim
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D005260:Female; D005994:Glycerophosphates / Q000096:biosynthesis; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D007536:Isomerism; D007545:Isoproterenol; D050155:Lipogenesis; D008066:Lipolysis; D008279:Magnetic Resonance Imaging; D051379:Mice; D016254:Mutagenesis, Insertional; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism; D009929:Organ Size; D025203:Phosphofructokinase-1, Muscle Type / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis
D005994:Glycerophosphates; D007328:Insulin; D014280:Triglycerides; C029620:alpha-glycerophosphoric acid; D025203:Phosphofructokinase-1, Muscle Type; D007545:Isoproterenol