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Submitted on June 10, 2004
Accepted on September 15, 2004
Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham NC 27710, #Inserm Unite 584 - Hormone Targets, Faculte de Medecine Necker, Paris, France 75015, and Musculoskeletal Diseases Center, Jerry L. Pettis VA Medical Center, Loma Linda, CA 92357
* To whom correspondence should be addressed. E-mail: freem001{at}mc.duke.edu.
To delineate the roles of the lactogens and GH in the control of perinatal and postnatal growth, fat deposition, insulin production, and insulin action, we have generated a novel mouse model that combines resistance to all lactogenic hormones with a severe deficiency of pituitary GH. The model was created by breeding prolactin receptor (PRLR)-deficient (knockout) males with GH-deficient ("little") females. In contrast to mice with isolated GH- or PRLR-deficiencies, double mutant (lactogen-resistant and GH-deficient) mice on day 7 of life had growth failure and hypoglycemia. These findings suggest that lactogens and GH act in concert to facilitate weight gain and glucose homeostasis during the perinatal period. Plasma insulin, IGF-I and IGF-II concentrations were decreased in both GH-deficient and double-mutant neonates but were normal in PRLR-deficient mice at this age. Body weights of the double mutants were decreased markedly during the first 3-4 months of age, and adults had striking reductions in femur length, plasma IGF-I and IGF binding protein-3 concentrations, and femoral bone mineral density. By age 6-12 months, however, the double mutant mice developed obesity, hyperleptinemia, fasting hyperglycemia, relative hypoinsulinemia, insulin resistance, and glucose intolerance; males were affected to a greater degree than females. The combination of perinatal growth failure and late-onset obesity and insulin resistance suggests that the lactogen resistant/GH-deficient mouse may serve as a model for the development of the metabolic syndrome.
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