Drake, Mandy

Hadoke, Patrick

Dakin, Rachel Sarah

Medical Research Council (MRC)

British Heart Foundation

2013-12-10T10:18:13Z

2013-12-10T10:18:13Z

2012-11-30

In recent years there has been an explosion in the rates of obesity, defined as a body mass index greater than 30kg/ m2, and associated cardiovascular disease. Alterations in peripheral glucocorticoid metabolism have been suggested to play a role in the development of obesity. Obesity occurs in both sexes, but the risk of associated metabolic disturbance and vascular dysfunction is greater in men. Although there is no accepted definition of obesity in rodents, the term is used to describe animals with a significant increase in fat pad mass often achieved by feeding a high fat diet. Although animal models of obesity have been useful in delineating potential mechanisms linking obesity with its metabolic and vascular sequelae, most studies have been in male animals and, thus, have not addressed sex differences. Additionally, emerging evidence shows that obesity during pregnancy is associated with increased cardio-metabolic and vascular disease in offspring, although the processes underlying such ‘programming’ effects are unclear. This thesis addresses the hypothesis that exposure to postnatal, or maternal obesity will alter both metabolism and vascular function in mice. Male and female mice maintained on a high fat and sugar diet from 5 weeks of age had increased adipose tissue deposition in adulthood. However there were striking sex differences in glucose homeostasis, mRNA levels and glucocorticoid metabolism, with males being more severely affected. Treatment of male mice with 17β-estradiol ameliorated a number of the effects of the high fat diet, including weight gain and altered glucose homeostasis; additionally estradiol altered glucocorticoid metabolism in the adipose so that it resembled that of females. Suprisingly, given the changes in metabolism, obesity in adult mice produced only small changes in vascular function and did not alter vascular remodelling following injury. The effects of maternal obesity were studied using male offspring aged 3 and 6 months. The offspring of obese mothers had similar body weight, adiposity, plasma lipid and plasma hormone concentrations to controls. In contrast, exposure to obesity in utero was associated with receptor specific changes in agonist-mediated contraction and decreased endothelium-dependent relaxation in male offspring. Despite these changes in vascular function, no alterations in blood pressure or vascular remodelling following injury were present. These results demonstrate that the more profound changes in glucose-insulin homeostasis associated with obesity in male humans can be recapitulated in rodent models and imply that estradiol plays a role in protecting the metabolism of female mice, potentially by alteration of glucocorticoid metabolism. Despite altered metabolism in postnatal obesity vascular function remained normal suggesting metabolic and vascular dysfunction are not intrinsically linked. Conversely, maternal obesity did not cause any overt changes in offspring metabolism but caused vascular dysfunction implying these parameters can be programmed independently.

http://hdl.handle.net/1842/8256

en

The University of Edinburgh

Maternal diet-induced obesity in C57BL/6 mice alters vascular function in their offspring but not metabolism or vascular remodelling after intravascular injury. R.S. Dakin, P.W.F. Hadoke, B.R. Walker, J.R. Seckl, A.J. Drake. J. DOHaD (2011); 2 (s1): PI- 019

Diet-induced obesity is associated with sex-specific differences in glucocorticoid metabolism.. R.S. Dakin, J.R. Seckl, P.W.F. Hadoke, B.R. Walker, A.J. Drake. Endocr Rev (2011); 32 (3): P2-442

Diet-induced obesity with metabolic dysfunction does not alter vascular function or remodelling in young C57BL/6 mice. R.S. Dakin, A.J. Drake, B.R. Walker, J.R. Seckl, P.W.F. Hadoke. Endocrine Abstracts (2011);25 P145

Maternal obesity is associated with sex-specific effects on offspring metabolism. R. Dakin, L. Liu, V. King, P. Hadoke, B. Walker, J. Seckl, A. Drake. Oral presentation. Power of programming meeting, Munich, May 2010.

Diet-induced obesity in C57BL/6 mice is associated with sex-specific changes in glucocorticoid metabolism. R.S. Dakin, P.W.F. Hadoke, J.R. Seckl, B.R. Walker, A.J. Drake. Endocrine Abstracts (2010); 21 P185

Diet-induced obesity is associated with sex-specific alterations in metabolic, but not vascular, function in mice. R.S. Dakin, B.R. Walker, J.R. Seckl, P.W.F. Hadoke, A.J. Drake. Oral presentation. Scottish Society for Experimental Medicine meeting, Aberdeen, May 2009.

obesity

programming

steroids

glucocorticoids

vascular function

Effects of postnatal and maternal diet-induced obesity on physiology and vascular function

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy