Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat.
We recently created a new model of murine obesity through transgenic ablation of brown adipose tissue (BAT) using a tissue-specific toxigene (6). The goal of the present study was to further define the altered glucose homeostasis and insulin resistance in these transgenic animals. Despite an approximately 30% increase in total body lipid, no abnormalities were observed in 6-week-old transgenic animals. At the age of 22-26 weeks, marked obesity in transgenic mice was associated with significant increases in blood glucose and plasma insulin levels and an abnormal response to both intraperitoneal glucose and insulin tolerance tests. Glucose transport in soleus muscle was reduced, with the response to insulin stimulation blunted by up to 85% in males and 55% in females. The total number of insulin receptors was decreased by 36% in muscle and 59% in adipose tissue of transgenic animals. Insulin receptor tyrosine kinase activity, which was assessed following maximal insulin stimulation in vivo, was reduced in transgenic animals by 59% in muscle and 56% in fat. GLUT4 mRNA and protein was unchanged in muscle of transgenic animals compared with in that of controls but was significantly reduced in adipose tissue. In conclusion, primary BAT deficiency results in the development of glucose intolerance or diabetes and severe insulin resistance with both receptor and postreceptor components. These animals should be a useful model for studies of obesity-linked diabetes and insulin resistance and related complications.
Hamann
A
A
Division of Endocrinology and Metabolism, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Benecke
H
H
Le Marchand-Brustel
Y
Y
Susulic
V S
VS
Lowell
B B
BB
Flier
J S
JS
D000273:Adipose Tissue / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000033:anatomy & histology*; D000375:Aging; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004167:Diphtheria Toxin / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000378:metabolism; D012016:Reference Values; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001786:Blood Glucose; D004167:Diphtheria Toxin; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003847:Deoxyglucose; D011972:Receptor, Insulin