|dc.description.abstract||5a-Reductase 1 (5aR1) metabolises steroids such as glucocorticoids and androgens
and is highly expressed in the livers of mice. Genetic disruption of 5aR1 leads to
adverse metabolic consequences in mice and pharmacological inhibition in humans
induces peripheral insulin resistance. I hypothesised that these effects are due to
increased hepatic glucocorticoid action and firstly set up an experimental paradigm
using A-348441, a liver-selective glucocorticoid receptor antagonist, to assess the
contribution of hepatic glucocorticoid action. A-348441 was then utilised to assess
whether changes in hepatic glucocorticoid signalling underpinned metabolic changes
in: 1) a genetic model where the gene for 5aR1 has been disrupted, and 2) a
pharmacological model using dutasteride, a dual 5aR1, R2 inhibitor.
Previous work with A-348441 has demonstrated it can lower blood glucose levels in
ob/ob mice. However, monogenic models of obesity are not fully representative of
idiopathic obesity, which is commonly related to diet. Therefore, I utilised a mouse
model of high fat dietary challenge to determine the effects of A-348441 in a more
relevant model. High fat diet worsened metabolic indices such as body weight and
weight gain, adipose tissue depot mass, fasting insulin and insulin response to a
glucose challenge. A-348441 improved metabolic health of mice on high fat diet,
preventing high fat-induced body weight gain, total white adipose depot weight gain
and attenuating high fat-induced elevations in fasting plasma insulin, fasting glucose
and insulin response to a glucose tolerance test. Importantly, hepatic glucocorticoid
receptor antagonism did not change plasma corticosterone concentrations, indicating
that glucocorticoid receptor antagonism was limited to the liver and thus
demonstrating that hepatic glucocorticoid action plays a major role in high fat dietinduced
Using A-348441, I then went on to test the contribution of hepatic glucocorticoid
action to the adverse metabolic phenotype in wild-type and 5aR1 knockout mice also
under a high fat dietary challenge; two timescales were explored – 10 weeks with A-
348441 administered from the start and 6 months with A-348441 introduced after 5
months of high fat diet. 5aR1 knockout mice were overall more insulin resistant and
had fattier livers than the wild-type mice at 10 weeks regardless of diet consumed.
High fat diet overall worsened metabolic indices - increasing body weight, weight
gain, adipose tissue depot mass, fasting insulin and insulin response to a glucose
challenge in both genotypes and at both time points.
Hepatic glucocorticoid receptor antagonism in 5aR1 knockout mice prevented high
fat diet-induced metabolic consequences as expected in the 10-week high fat diet
model, but not in the 6-month experiment; hyperinsulinaemia and weight gain were
attenuated in the 10-week high fat diet model but not the 6-month high fat diet model,
suggesting hepatic glucocorticoid receptor antagonism can prevent, but not reverse,
high fat diet-induced metabolic consequences. However, A-348441 did not have a
bigger effect on ameliorating the worsened metabolic state of the 5αR1 knockout mice.
This suggests that increased hepatic glucocorticoid action does not underpin the
adverse phenotype reported in the 5aR1 knockout mice.
Dutasteride is a dual 5aR inhibitor prescribed to men for benign prostate hyperplasia
or prostate cancer. I then recapitulated the human experiment where 5aR was
pharmacologically inhibited and investigated the effects of dutasteride in mice.
Inhibition of 5aRs in mice impaired insulin sensitivity, with increased insulin response
to glucose tolerance test and also increased liver triglyceride levels; body weight, total
adipose depot weight, fasting insulin, fasting glucose or glucose response to a glucose
tolerance test were not changed by dutasteride. A-348441 reduced this
hyperinsulinaemia but, as in other models, did not reduce the increased liver
triglyceride levels. This suggests hepatic glucocorticoid action plays a substantial role
in the development of insulin resistance caused by 5aR inhibition, but not in the
development of hepatic steatosis.
Therefore, adverse metabolic changes as a result of 5aR1 inhibition with dutasteride
may be driven by altered hepatic glucocorticoid metabolism. Furthermore, metabolic
changes caused by lifelong 5aR1 disruption are not responsive to short-term hepatic
glucocorticoid receptor antagonism and altered androgen signalling may play a greater
role. In conclusion, targeting the hepatic glucocorticoid receptor may be beneficial in
restoring metabolic homeostasis in diet-induced obesity.||en