Endocrine Abstracts (2004) 7 OC34

POMC haploinsufficiency in mice can cause obesity and reduced adrenal function

AP Coll, BG Challis, GSH Yeo, K Snell & S O'Rahilly

Department of Clinical Biochemistry and Medicine, Addenbrooke's Hospital, Cambridge, UK.

Pro-opiomelanocortin (POMC) deficiency in mice and humans results in a syndrome of severe obesity, hyperphagia and adrenal insufficiency. We have used mice heterozygous for a null mutation in the Pomc allele (Pomc+/-) to determine if POMC haploinsufficiency results in disordered energy homeostasis or adrenal hypofunction.

When fed standard lab diet (SLD, 4.5% fat) Pomc+/-were similar in weight to wild type (WT) mice throughout life. Provision of a high fat diet (HFD, 40% fat) had no impact on the body weight of WT mice. However, on a HFD Pomc+/- developed obesity becoming significantly heavier than SLD fed heterozygous mice (weight at six months, 28.5+1.3 (mean +S.E.M.) vs. 34.9+1.5 g, p<0.05). On SFD, WT and Pomc+/- had a similar energy intake , but on HFD Pomc+/- had a significantly higher energy intake compared to wild type (70.9+4.1 vs. 59.6+3.5 kJ/day, p<0.05).

Pomc+/- have smaller adrenal glands than WT mice (weight of single gland, 2.0+0.2 vs. 2.7+0.2 mg, respectively, p<0.05) but gross histological appearance is identical. Corticosterone levels at 0900 in WT and Pomc+/- were similar (73+12 vs. 42+13 ng/ml, respectively, n.s.) but levels measured at 1700 had risen to 242+16ng/ml in WT compared to 78+12 ng/ml in Pomc+/- (p<0.05).

CRH stimulation test (1microg, subcutaneous) caused a significantly higher rise in corticosterone in WT compared to Pomc+/- mice ( 795+97 vs. 516+64 ng/ml, respectively, p<0.05). ACTH stimulation test (10microg/kg mice, intraperitoneal) caused corticosterone to rise to 260+55ng/ml in WT compared to 142+20 ng/ml in Pomc+/- ( p=0.06).

These data demonstrate that under certain environmental conditions a single functional copy of POMC gene is not sufficient for maintaining normal energy homeostasis. In addition, POMC haploinsufficiency results in a reduced diurnal variation in corticosterone levels and a subnormal response to dynamic CRH and ACTH testing.

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