Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficientLepob/obmice.
Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lepob/ob) develop hyperinsulinemia prior to onset of obesity and glucose intolerance. Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis inLepob/obmice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction inLepob/obmice on circulating insulin, body composition, and glucose homeostasis.



Leptin expressing (Lepwt/wt) mice lacking 3 insulin alleles were crossed withLepob/obmice to generateLepob/obandLepwt/wtlittermates lacking 1 (Ins1+/+;Ins2+/-), 2 (Ins1+/+;Ins2-/-) or 3 (Ins1+/-;Ins2-/-) insulin alleles. Animals were assessed for body weight gain, body composition, glucose homeostasis, and islet morphology.



We found that in youngLepob/obmice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75-95% and attenuated body weight gain by 50-90% compared toIns1+/+;Ins2+/-;Lepob/obmice. This corresponded with ∼30% and ∼50% reduced total body fat inIns1+/+;Ins2-/-;Lepob/obandIns1+/-;Ins2-/-;Lepob/obmice, respectively. Loss of 2 or 3 insulin alleles in youngLepob/obmice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles inLepwt/wtmice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance.



Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity inLepob/obmice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: dsouzaa@interchange.ubc.ca.
Anna M
AM
D'souza
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: james.d.johnson@ubc.ca.
James D
JD
Johnson
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: susanne.clee@ubc.ca.
Susanne M
SM
Clee
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada; Department of Surgery, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: tim.kieffer@ubc.ca.
Timothy J
TJ
Kieffer
D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D006946:Hyperinsulinism; D007328:Insulin; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009765:Obesity
D007328:Insulin; D020738:Leptin
Hyperglycemia; Hyperinsulinemia; Lepob/ob; Obesity