January 2008

Document Type


Degree Name



Dept. of Physiology and Pharmacology


Oregon Health & Science University


In low birth weight babies, accelerated childhood growth amplifies risk of adult cardiovascular and metabolic diseases, but roles of rapid growth per se vs obesity typically associated with accelerated growth are unknown. In microswine offspring exposed to maternal protein restriction (MPR) in late gestation plus early lactation, we examined the hypotheses that: 1) MPR would lead to accelerated growth; 2) accelerated growth would be associated with development of obesity; 3) altered adipocyte size and function would be observed concurrently with obesity; 4) these effects would be related to altered hypothalamic-pituitary-adrenal (HPA) axis and/or tissue-level glucocorticoid (GC) function; and 5) these effects are programmed indirectly as consequences of accelerated growth. Compared to Normal Protein Offspring (NPO) controls, Low Protein Offspring (LPO) have reduced weight at birth and at 2 wks but similar weights as juveniles. In LPO, growth rates (weight and length gain) are reduced from 2-5 wks but increased from 6-12 wks vs NPO. Also over 6-12 wks, feed intake in LPO was higher by ~16% and feed utilization efficiency was increased. Percent body fat and lean mass were reduced in LPO at 6 wks. By 11wks, % body fat and lean mass in LPO were not different, reflecting significantly increased accrual rates for both fat and lean tissue. Post-weaning Feed Limitation (FL) applied in a subset of offspring (preliminary data), slowed growth rate in both sexes but prevented the increased rate of fat mass accrual only in females. HPA axis and local cortisol production and activity were not affected by MPR or by post-weaning FL except for a transient decrease in plasma cortisol at 2 wks. In juveniles, fasting plasma glucose was increased in LPO males but decreased in LPO females compared to sex-matched controls; FL did not affect plasma glucose, suggesting that fasting plasma glucose is programmed directly by MPR. Fasting plasma glucose also appears to be regulated independently of adipose tissue dysfunction. In females, FL after MPR causes altered LPL transcription in a manner suggesting potential for increased lipid deposition in Intra-abdominal (IAT) vs. Subcutaneous (SAT) Adipose Tissue. Adipocyte size in IAT, while not significantly different, tended to be decreased in LPO vs NPO. FL reduced adipocyte size similarly in all groups. Adiponectin mRNA was decreased in both fat depots in LPO vs NPO. FL restored adiponectin mRNA levels to normal in IAT, but not in SAT, suggesting that impaired adiponectin transcription is a secondary effect of accelerated growth in IAT, but is programmed directly by MPR in SAT. TNF-α mRNA was not altered by MPR in either depot and was not changed by FL. Adiponectin mRNA expression was reduced in SAT vs IAT. In summary, perinatal MPR programs accelerated overall body growth and adipose tissue accrual, accompanied by reduced adiponectin expression without obesity and without adipocyte hypertrophy. Accelerated growth is accompanied by hyperphagia and increased feed utilization efficiency; these data do not preclude that hyperphagia may be secondary to growth acceleration mechanisms. Neither HPA axis activation nor local GC production were involved in accelerated growth or adipose tissue function. Some programmed MPR effects are direct, while others are programmed indirectly as a consequence of accelerated growth. Reduced adiponectin transcription may represent one important link between early development and later risk of disease.




School of Medicine



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