DOI 10.

1515/hmbci-2013-0038 Horm Mol Biol Clin Invest 2013; 15(2): 71–80

Radhika V. Seimon, Nikita Hostland, Stephanie L. Silveira, Alice A. Gibson and

Amanda Sainsbury*

Effects of energy restriction on activity of the

hypothalamo-pituitary-adrenal axis in obese
humans and rodents: implications for diet-
induced changes in body composition
Abstract weeks or months in severe or moderate energy restriction
in order to reduce excess weight, and given that increases
Background: Obesity treatments aim to maximize fat loss, in glucocorticoid function can have significant effects on
particularly abdominal or visceral fat, without compro- body composition within weeks to months.
mising lean or bone mass. However, the literature con-
tains numerous examples of obesity treatments that – in Keywords: animals; caloric restriction; HPA axis; humans;
addition to fat loss – result in loss of lean mass and/or obesity.
bone mass.
Materials and methods: Because of the known effects of
*Corresponding author: Amanda Salis (nee Sainsbury), The Boden
energy restriction to increase activity of the hypothalamo- Institute of Obesity, Nutrition, Exercise and Eating Disorders,
pitutiary adrenal (HPA) axis in lean humans and animals, Sydney Medical School, The University of Sydney, Camperdown
and because increases in circulating glucocorticoid levels NSW 2006, Australia, Phone: +61 4 23777801,
could potentially contribute to adverse body composi- E-mail: [email protected]; and School of Medical
tional changes with obesity treatments, we conducted a Sciences, University of NSW, Kensington, Sydney, NSW 2052,
Australia
systematic PubMed search to determine whether HPA axis
Radhika V. Seimon, Nikita Hostland, Stephanie L. Silveira and
activation also occurs in response to energy restriction in Alice A. Gibson: The Boden Institute of Obesity, Nutrition, Exercise
obese humans and animals. and Eating Disorders, Sydney Medical School, The University of
Results and conclusions: In most studies in obese hu- Sydney, Sydney, NSW 2006, Australia
mans, short-term severe energy restriction increased cir-
culating cortisol levels, and this response was also seen
in two longer-term human studies involving severe or mo-
derate energy restriction. These findings parallel studies Introduction
on short- or long-term energy restriction in obese rodents,
with most studies showing increases in circulating corti- Obesity is a condition defined as abnormal or excessive fat
costerone concentrations, and no change or actual increa- accumulation and has been identified as a risk factor for
ses in hypothalamic expression of corticotropin-releasing a number of disorders, including type 2 diabetes [1] and
hormone, urocortin 3 or their receptors. However, a signi- cardiovascular diseases [2]. The worldwide prevalence of
ficant proportion of studies involving longer-term severe obesity continues to increase and has more than doubled
or moderate energy restriction in obese humans showed since 1980.
no change or decreases in HPA axis function. There was An important aspect of curbing the impact of the
variability among human studies in the duration of ener- obesity epidemic is providing effective long-term treat-
gy restriction and timing of the HPA axis investigations ments. The aim of obesity treatments is to maximize the
(i.e., during energy restriction, or after a period of post-re- loss of fat mass, particularly abdominal or visceral fat
striction weight maintenance). In order to unambiguously mass, without compromising lean body mass or bone
determine changes in HPA axis function with energy re- mass. However, the literature contains numerous exam-
striction in obese humans, it will be important to assess ples of obesity treatments that – in addition to induc-
HPA axis function at multiple time points during energy ing fat loss – result in loss of lean mass and/or bone
restriction, given that obese individuals may spend many mass, particularly when supervised strength training is
72 Seimon et al.: Energy restriction and the HPA axis in obesity

not incorporated into the treatment regime [3–7], when in depth only those articles that included investigation of
dietary protein intake falls below certain critical levels [8], the effect of energy restriction on the HPA axis in obese
and possibly also when weight loss is rapid, as in severely humans or animals (mice and rats), as stated in the article
energy-restricted diets [9], or as a result of some forms title or abstract. Sixteen human and 10 animal articles met
of bariatric surgery [10]. Understanding the mechanisms these criteria and were thus included in our review. These
underpinning changes in body composition in response articles are cited in the sections below entitled “Effects
to obesity treatments could lead to improved clinical out- of energy restriction on activity of the HPA axis in obese
comes from such treatments. humans”, and “Effects of energy restriction on activity of
We hypothesise that increased activity of the hypo- the HPA axis in obese rodents”.
thalamo-pituitary-adrenal (HPA) axis in response to Before outlining the results of our systematic litera-
energy restriction in obese people may contribute to less ture search, we will first provide an overview of the HPA
than optimal body compositional outcomes. The ration- axis, as well as the effects of obesity per se and eating
ale for this hypothesis is that energy restriction in lean on activity of this axis, as this provides important back-
humans or animals is known to up-regulate activity of ground to our literature review.
the HPA axis, with resultant increases in circulating
glucocorticoid levels [11]. Moreover, because glucocorti-
coids per se can cause accretion of white adipose tissue
– particularly visceral adipose tissue – as well as loss of Overview of the HPA axis
lean tissue and bone mass in humans and animals, such
increases in circulating glucocorticoid levels probably The HPA axis is a major neuroendocrine system that helps
contribute to the loss of lean tissue and bone in severely to protect against stressors by regulating the secretion of
energy-restricted people (e.g., patients with anorexia glucocorticoids [12]. Stress induces the release of cortico-
nervosa or elite gymnasts), as well as the preferen- tropin-releasing hormone (CRH) from the paraventricular
tial accretion of central fat with re-feeding in anorexia nucleus (PVN) of the hypothalamus. CRH is released into
nervosa [11]. One might argue that an obese individual the hypophyseal portal system and is transported to the
undergoing energy restriction to lose excess weight is pars distalis in the anterior lobe of the pituitary gland,
under a less extreme form of nutritional stress than an where it stimulates the secretion of adrenocorticotropin
already lean or underweight individual in severe energy (ACTH) from the anterior pituitary. ACTH, in turn, stimu-
restriction caused by anorexia nervosa or competitive lates glucocorticoid production from the adrenal cortex,
sports requirements. However, because obesity per se is and glucocorticoids are transported in the circulation
already associated with heightened activity of the HPA bound to corticosteroid-binding globulin (CBG). The avail-
axis, as will be briefly discussed below, any effects of ability of glucocorticoids in target tissues is dependent on
energy restriction on HPA axis activity in obesity may not activity of the enzyme 11β-hydroxysteroid dehydrogenase
be negligible. (11β-HSD). The 11β-HSD1 isoform converts the inactive
In light of these considerations, we conducted a sys- glucocorticoids (cortisone in humans and 11-dehydrocor-
tematic search of the literature in the PubMed database ticosterone in rodents) into their active form (cortisol in
from 1975 to June 2013 in order to ascertain the effects humans and corticosterone in rodents), and the 11β-HSD2
of energy restriction on activity of the HPA axis in obese isoform inactivates cortisol and corticosterone [13]. Gluco-
animals and humans. Our search strategy included the corticoids exert actions in target tissues by binding to and
following Medical Subject Heading (MeSH) terms: [diet, activating the glucocorticoid receptor. Glucocorticoids
reducing OR diet, weight loss OR caloric restriction OR participate in the control of whole body homeostasis and
obesity/diet therapy OR food deprivation OR body weight the response to stress, and play a key role in regulating
(only in animal search)] AND [corticotropin-releasing basal activity of the HPA axis. The glucocorticoid recep-
hormone OR receptors, corticotropin-releasing hormone tor initiates or represses gene transcription, and induces
OR corticotroph OR receptors, corticotropin OR glucocorti- negative feedback of the HPA axis, for termination of the
coid OR receptors, glucocorticoid OR adrenocorticotropic stress response, by acting on the hypothalamus and the
hormone OR hydrocortisone OR corticosterone OR cortico- pituitary gland [14]. The inhibitory glucocorticoid feed-
releasing factor (only in animal search)] AND (obesity). back on the HPA axis limits duration of the total tissue
We limited our search to articles in English and studies in exposure to glucocorticoids, thus minimizing catabolic,
humans and animals. The search yielded 105 human and anti-reproductive and immunosuppressive effects of these
741 animal articles. We retrieved the full text and reviewed hormones.
 Seimon et al.: Energy restriction and the HPA axis in obesity 73

Obesity is associated with section provides an overview of the effects of daily

rhythms in food intake on activity of the HPA axis. This
dysregulation of the HPA axis knowledge is important, because the recent nutritional
status of research subjects at the time of investigation can
Previous studies have shown that obesity is associated
profoundly influence results.
with HPA axis dysregulation that may originate from
Food intake has been shown to be a synchronizer of
increased forward drive, decreased sensitivity to negative
diurnal rhythm of the HPA axis, a rhythm that is character-
feedback regulation, or altered sensitivity of peripheral
ized in humans by maximum glucocorticoid levels in the
tissues such as fat and skeletal muscle tissue to gluco-
early morning and minimum levels at night [29–31]. Under
corticoids [15, 16]. Obese humans show a hypersensitive
normal circumstances, surging levels of cortisol enter the
response to stimulation of the HPA axis, the magnitude of
bloodstream after a midday or evening meal, contributing
this exaggerated response being dependent on fat distri-
to the undulating nature of daily HPA axis activity [30, 32].
bution [17, 18]. After physical or psychological stressors, or
Fasting is a state of stress [29] that alters the normal
after exogenous administration of CRH, obese individuals
HPA axis rhythm. If overnight fasting is extended through-
showed exaggerated circulating ACTH and glucocorticoid
out the day, circulating cortisol levels peak later in the
levels [17, 19]. This exaggerated response was significantly
afternoon and follow an overall higher, flattened profile
greater in those obese people who have a more visceral
[32–34]. This change likely contributes to energy homeo-
distribution of body fat than those with a more subcuta-
stasis in cases of insufficient exogenous energy intake,
neous distribution [17]. Greater visceral adiposity is also
because hypercortisolemia promotes an appetite for cal-
associated with a higher HPA axis response in lean people
orie-dense, highly palatable food and processes such as
[19]. Sex also plays an important role in determining HPA
gluconeogenesis to convert stored forms of energy into
axis response, where cortisol exposure is inversely related
useable glucose [29, 33, 35–38].
to fat mass index (calculated as fat mass/height2 in kg/m2)
The exact mechanism by which the HPA axis responds
in men and waist to hip ratio in women [18, 20–23].
to acute changes in food intake remains elusive. It seems
While the exact direction(s) of causality in this asso-
that the type of macronutrient ingested plays an impor-
ciation between visceral adiposity and HPA response is
tant role in HPA axis stimulation. High protein meals
unclear, the relationship may be caused by the physiology
stimulate a significantly higher cortisol secretion than do
of visceral fat, which contains a higher density of glucocor-
high carbohydrate or high fat meals [39–41]. Although sci-
ticoid receptors than subcutaneous fat without an increase
entists are still unclear of how a signal reaches the HPA
in binding affinity [24]. This could in turn influence glu-
axis once food has been ingested, one study has shown
cocorticoid production and subsequent negative feedback
that nasogastric compared to intravenous administra-
to the brain. Indeed, it has been shown that people with a
tion of nutrients induces a much more significant cortisol
greater visceral fat distribution may have increased pitui-
response, suggesting that the signalling emanates from
tary sensitivity to CRH [18]. Another factor that may contrib-
the stomach or duodenum before the metabolites enter
ute to the observation of increased HPA activity in people
the blood stream [40].
with more adiposity is that obesity is characterized by a
While activity of the HPA axis is influenced by the
state of chronic mild inflammation [25, 26], with enhanced
presence of food, human and animal studies (as discussed
circulating levels of inflammatory markers, including
below) have shown that energy restriction, be it severe or
cytokines [27]. Cytokines – like stress – have been shown
moderate, also affects the HPA axis on several levels.
to stimulate the HPA axis at the level of the hypothalamus,
anterior pituitary gland, and the adrenal cortex [14, 28].
In summary, obesity in humans – particularly visceral
obesity – is associated with increased activity of the HPA
axis, and this may be due in part to specific qualities of
Effects of energy restriction on
visceral adipose tissue. activity of the HPA axis in obese
humans
The HPA axis and food intake A number of studies have looked at the effect of short-
term periods of severe energy restriction on circulating
Before examining the effects of long-term energy restric- or urinary cortisol levels in obese humans, with con-
tion, as in ‘dieting’ in obese humans and animals, this flicting evidence. Two studies have shown a decrease in
74 Seimon et al.: Energy restriction and the HPA axis in obesity

circulating cortisol levels, after 48 h [42], or urinary cor- cortisol levels or function of the HPA axis, with published
tisol levels after 3 days [43] of short-term severe energy studies reporting no change, inhibitory or stimulatory
restriction, while three other studies using short-term effects. Moderate (30%) energy restriction in overweight
total fasting reported an increase in circulating cortisol and obese individuals over a period of 12 weeks resulted
[44–46]. These latter studies involved an 84-h total fast in no significant differences in 24-h urinary free cortisol/
[44] or 6–11 days of starvation in obese men [45, 46], and cortisone, circulating CBG or free cortisol levels during a
were found to increase circulating cortisol levels [44–46] – low dose ACTH simulation test [52]. Similarly, 6 months of
both total and unbound [46] – with no change [45] or only moderate energy restriction (a 250–350 kcal/day deficit)
a slight increase [46] in total or free urinary cortisol. On in obese women had no effect on circulating levels of
balance, the majority of the studies (three out of five) that cortisol [53]. These findings support a shorter-term study
have investigated the effects of severe short-term energy that showed no differences in salivary cortisol levels fol-
restriction on circulating cortisol levels in obese humans lowing 18 days on a moderately energy-restricted diet of
have shown significant increases in this parameter. 1000 kcal/day [54]. Also, 3 months on a moderately
There have been somewhat mixed results with longer- energy-restricted diet of 1000 kcal/day, followed by a
term severe energy restriction on HPA axis function in period where participants were transitioned back to solid-
obese humans. The majority of studies report no change foods over 2 weeks and then spent 3 months on a weight
in function. Four weeks of severe energy restriction of maintenance diet, had no effect on cortisol production
~380 kcal/day in obese female identical twins had no rate, either absolute values or normalized to fat free mass
effect on circulating levels of cortisol [47]. In addition, [55]. However, in that study cortisol production rate nor-
a severely energy-restricted diet to achieve a weight loss malized to fat mass or intra-abdominal fat mass increased
of > 10% of initial body weight, followed by a 1-week re- by 40% and 100%, respectively, after weight loss [55].
feeding regime, resulted in no change in circulating cor- While these three studies involving moderate energy
tisol levels in obese individuals [48]. Similarly, 3 weeks restriction showed no clear changes in HPA axis func-
on a severely energy-restricted diet of ~600 kcal/day, fol- tion, another study of a 90-day diet of 800–1500 kcal/day
lowed by 1 week of weight maintenance and then 2 weeks in obese women showed decreased ACTH and cortisol
of ad libitum feeding, did not alter circulating cortisol levels measured during an oral glucose tolerance test [56].
levels in obese men [45]. Further, following 12-weeks on In contrast, moderate energy restriction (a 500 kcal/day
a severely energy-restricted diet of 800 kcal/day in obese deficit) over 10 weeks in obese men increased circulating
women, circulating ACTH levels and ACTH response to cortisol levels and decreased that of ACTH [57].
ovine CRH stimulation were unaltered relative to pre-diet Taken together, the available literature shows that
levels and did not differ between the obese participants energy restriction in obese adults results in disturbances
and lean controls [49]. However, in that study cortisol con- in HPA axis function, albeit the direction of change is not
centrations decreased after weight loss, and there was a clear. In most [44–46] but not all [42, 43] studies in obese
reduced cortisol response to ovine CRH stimulation [49]. humans, short-term severe energy restriction produced an
Another study also showed a decrease in circulating corti- increase in circulating cortisol levels, and this response
sol levels in obese males and females following a 4-week was also seen in women but not men in one longer-term
severely energy-restricted diet of ~380 kcal/day [50]. study involving severe energy restriction [51]. However,
While the majority of studies involving long-term severe most studies involving longer-term severe energy restric-
energy restriction in obese humans have shown either no tion in obese humans showed no change in HPA axis func-
change (three studies) or a decrease (two studies) in cir- tion [45, 47 ,48], and two studies suggested a decrease in
culating cortisol levels or cortisol response, this is not a activity of this axis [49, 50]. Similarly, longer-term moder-
unanimous finding. When obese participants were treated ate energy restriction in obese humans has been reported
with a severely energy-restricted diet of 450 kcal/day for to result in increases [57], no change [52–55] or decreases
16 weeks, followed by a hypocaloric diet for 32 weeks, cir- [56, 57] in HPA axis function.
culating cortisol levels increased in women, with no sig- A possible explanation for these widely discrepant
nificant change in men, when measured at 8 and 18 weeks findings in humans could be the time relative to the com-
after commencing the severely energy-restricted diet [51]. mencement of energy restriction when HPA axis func-
Similar to the findings with longer-term severe tion was measured. Many of the studies reviewed in this
energy restriction, it is also unclear if longer-term mod- section involved a period of post-diet re-feeding or weight
erate energy restriction, commonly used in the manage- maintenance prior to investigation of HPA axis function.
ment of overweight and obesity, influences circulating This experimental paradigm enables the effects of weight
 Seimon et al.: Energy restriction and the HPA axis in obesity 75

loss per se to be examined, independent of any effects of of 33% energy restriction, there was an increase in circu-
energy restriction. Indeed, certain adaptations to energy lating corticosterone concentrations in obese rodents. A
deficit, notably reduced metabolic rate and impaired similar effect was also seen with longer-term food depriva-
thyroid function, are seen when measured during energy tion. Following a 30% energy-restricted diet for 12-weeks,
restriction but not after a period of 10 days to 3 months in Otsuka Long Evans Tokushima Fatty rats had greater cir-
energy balance in weight-reduced individuals [58, 59]. As culating corticosterone concentrations when compared
such, it is reasonable to propose that HPA axis function with an unrestricted control group [68]. Interestingly,
may be different depending upon whether it is measured in that study no increase in corticosteronemia was seen
during energy restriction or following a period of weight when similar reductions in body weight, adiposity and
maintenance at the reduced body weight. Given that obese leptinemia were achieved by 12 weeks of wheel running
individuals may spend several months in severe or mod- [68]. It must be noted that one study in obese mice showed
erate energy restriction in order to reduce excess weight, a decrease (rather than an increase) in circulating corti-
and given that increases in glucocorticoid function can costerone concentrations following 6-weeks of food dep-
have significant effects on fat, lean and bone mass within rivation when compared with ad libitum-fed obese mice
2–3 months [60, 61], it is important to assess HPA axis [69].
function during energy restriction. Another factor that It can be seen from the above that short- or long-term
could contribute to the discrepant findings reported in energy restriction in obese rodents generally increases
this section is negative feedback regulation of the HPA circulating corticosterone levels. This effect is likely
axis; initial increases in circulating cortisol levels can mediated by the hypothalamus, because energy restric-
feed back on the pituitary gland and hypothalamus and tion influences hypothalamic expression of CRH or CRH
lead to eventual normalization or even inhibition of the receptors in obese rodents. One study looked at the effects
axis. Support for this concept comes from a study involv- of 48-h food deprivation on hypothalamic mRNA levels
ing continuous central administration of neuropeptide Y of urocortin 3 (Ucn3) and type 2 corticotropin-releasing
to rats [62], an experimental paradigm that mimics many hormone receptor (CRH2-R) in lean and obese Zucker rats
aspects of energy restriction [63]. This paradigm initially [70]. Ucn3 is part of the CRH family and binds specifically
increased circulating corticosterone and ACTH concen- to CRH2-R to decrease food intake, therefore playing an
trations, but subsequently led to normalization of these important role in responding to food-related stress. An
parameters, as well as down-regulation of hypothalamic interesting outcome of this experiment was that although
CRH mRNA expression [62]. In light of these considera- lean rats showed decreases in hypothalamic Ucn3 and
tions, we propose that a more complete understanding of CRH2-R mRNA levels in response to energy restriction,
HPA axis function with energy restriction in obese humans obese Zucker rats showed no change [70]. Similar findings
would be obtained if investigations were made at several were reported in another study, where CRH concentra-
time points during energy restriction. tions were measured in three regions of the hypothala-
mus of lean and obese mice: the arcuate nucleus (ARC),
paraventricular nucleus (PVN), and ventromedial hypo-
thalamus (VMH). Obese mice had half the CRH concentra-
Effects of energy restriction on tions in the ARC as lean mice in the un fasted state, but
– unlike their lean counterparts – they showed no change
activity of the HPA axis in obese (i.e., no decrease) in ARC CRH concentrations following
rodents 24 h of food deprivation [71]. While these studies showed
no effect of food deprivation on central CRH expression in
Studies in obese rodents have revealed a profound, pre- obese rodents, unlike food-deprived lean animals, another
dominantly stimulatory, impact of energy restriction on study has shown actual increases in brain CRH mRNA
activity of the HPA axis, either when compared to non- levels or activation of CRH-expressing hypothalamic cells
restricted obese controls, or when compared with effects with energy restriction in obese Zucker rats [72]. After
of energy restriction in lean rodents. 3, 6, 12 and 24 h of food deprivation, obese Zucker rats,
A number of studies have looked into the effect of compared to lean rats, showed a relative increase in CRH
overnight, short-term and longer-term food deprivation mRNA expression or cellular activation of CRH-expressing
on corticosterone concentrations in obese mice and rats neurons (as indicated by induction of c-fos expression) in
[64–67]. These studies showed that following 12 [65], 24 several brain regions, the changes being most pronounced
[66, 67] and 48 [67] h of fasting, or following 3 weeks [64] in the PVN. Obese rats also exhibited a marked increase in
76 Seimon et al.: Energy restriction and the HPA axis in obesity

type 1 corticotropin-releasing hormone receptor (CRH1-R) of energy restriction on activity of the HPA axis in lean
mRNA levels in the PVN starting at 6 h after fasting, com- humans and animals – obese humans and rodents some-
pared to lean rats, with no significant changes in CRH2-R times also display enhanced HPA axis activity in response
[72]. In light of the observation that energy deprivation to energy restriction. While further work is required to
in obese rodents generally increases circulating corticos- confirm this possibility, such an effect could potentially
terone levels [64–67], these findings of no change – or an contribute to less than optimal changes in body composi-
actual increase – in the hypothalamic expression of CRH, tion during energy restriction for the treatment of obesity.
Ucn3 or their receptors suggest that during energy restric- Not only does the binding of glucocorticoids to glu-
tion in obesity, the HPA axis may exhibit impaired nega- cocorticoid receptors produce effector responses that
tive feedback regulation at the level of the hypothalamus. have implications for metabolism and appetite, it also is
While obese rodents generally show energy restric- involved in the regulation of adipocyte and myocyte syn-
tion-induced increases in circulating corticosterone levels thesis, as well as regulating osteoblasts and osteoclasts.
and no decrease or an actual increase in central expression Glucocorticoids, through their interaction with insulin,
of CRH or CRH receptors, obese mice have been shown to promote the differentiation of pre-adipocytes into mature
have a decreased pituitary content of ACTH following a sig- fat cells as well as stimulating lipoprotein lipase activ-
nificant period of energy restriction. A group of genetically ity, which facilitates fat accumulation, particularly in the
obese ob/ob mice were put on an energy-restricted diet at abdomen [33, 74, 75]. High levels of glucocorticoids inhibit
5 weeks of age, when their weights were slightly over myocyte synthesis and promote breakdown through stim-
normal weight (overweight) [73]. Under normal circum- ulating protein catabolism pathways [33, 76]. This process
stances, adult obese mice were found to have roughly is further accelerated in the absence of insulin [77].
14 times higher levels of ACTH in the pituitary gland than This would most likely be seen in the fasting scenario,
lean mice. However, after 7 weeks of caloric restriction, where insulin levels are reduced and the body needs to
the obese mice showed pituitary ACTH levels nine times convert stored energy to useable energy [76]. Addition-
less than their obese, non-restricted counterparts, as well ally, the reduced circulating insulin concentrations typi-
as a significant decrease in ACTH secretion from the iso- cally observed during weight loss interventions in obese
lated perifused pituitary gland. These differences in pitui- individuals might therefore be expected to enhance the
tary ACTH levels between lean and obese mice were not catabolic effects of glucocorticoids on myocytes. Further
reflected by differences in plasma ACTH and corticosterone to effects on adipocytes and myocytes, glucocorticoids
levels [73]. This study did not report on the effect of energy promote apoptosis in osteobalasts and osteocytes, which
restriction on circulating ACTH levels in obese mice. would be expected to decrease bone formation, as well as
In summary, the HPA axis of obese rodents shows prolonging the lifespan of osteocalsts, which would be
marked changes in response to short- or longer-term expected to increase bone resorption [78].
energy restriction, with most but not all studies showing In keeping with the effects of glucocorticoids on fat,
increases in circulating corticosterone concentrations muscle and bone cells observed in vitro, lean men and
compared to non-restricted levels, and no change or women taking a high dose of oral glucocorticoid treatment
actual increases in hypothalamic expression of CRH, ( ≥ 40 mg/day of a prednisolone equivalent) for 2 months
Ucn3 or their receptors. Additionally, one study from 1975 showed a 10% increase in fat mass, a 10% decrease in lean
showed a decrease in pituitary ACTH levels or secretion body mass, and significant decreases in bone mineral
with longer-term energy restriction in obese mice. density and bone mineral content in the absence of effects
on body weight [60]. Longer-term use (more than 60 days)
of oral glucocorticoids is associated with self-reported
weight gain in over 60% of patients, including those on
Effects of changes in activity of the lower doses (e.g., 10 mg/day prednisone for 6 months),
HPA axis on body composition and weight gain is the most commonly reported adverse
event in patients taking glucocorticoids [61]. Additionally,
It is often assumed that activation of the HPA axis in people with Cushing’s syndrome, associated with primary
response to energy restriction would only be observed hypercortisolism, exhibit hyperphagia, weight gain, vis-
under cases of extreme stress, such as in lean humans ceral obesity and muscle wasting [19, 76, 79], further
with anorexia nervosa or cachexia, or in lean animals. demonstrating a primary role of increased glucocorticoid
However, our review of the literature in obese humans and action in the propensity to store fat (particularly central
rodents shows that – as is the case for the known effects fat) at the expense of lean tissues.
 Seimon et al.: Energy restriction and the HPA axis in obesity 77

It remains to be determined whether any changes in case in several human studies hereby reviewed. Addi-
circulating glucocorticoid concentrations with energy tionally, correlating changes in HPA axis function with
restriction in obese individuals contributes to adverse changes in parameters of body composition, such as fat
effects on body composition. mass and distribution, lean body mass, muscle strength
and bone mineral content, could shed light on the role of
altered HPA axis function, if any, in mediating favourable
or unfavourable changes in body composition in response
The gap in knowledge and to obesity treatments. Such knowledge could aid in the
significance quest for obesity treatments that maximize the loss of fat
mass, particularly abdominal or visceral fat mass, without
Our review of the literature has not ruled out the possi- compromising lean body mass or bone mass.
bility that energy restriction in obese individuals is per-
Acknowledgments: We are grateful to the National Health
ceived as a nutritional stress, resulting in indications of
& Medical Research Council of Australia for financial
enhanced HPA axis function in most rodent studies and in
support during the preparation of this work, via a pro-
some – but certainly not all – human studies. Studies in
ject grant (AS and RVS) and a fellowship (AS), as well as
obese humans on effects of energy restriction on HPA axis
for the financial support of an Australian Postgraduate
function showed a great deal of variability, with reports
Award to AAG.
of increased, unchanged or decreased circulating cortisol
levels. As recent nutritional status influences function of
Conflict of interest statement: Amanda Sainsbury-Salis is
the HPA axis, and because changes in HPA axis activity
the author of The Don’t Go Hungry Diet (Bantam, Australia
can be masked by feedback regulation of the axis by gluco-
and New Zealand, 2007) and Don’t Go Hungry For Life
corticoids, we propose that a more complete understand-
(Bantam, Australia and New Zealand, 2011). None of the
ing of HPA axis function with energy restriction in obese
authors had a conflict of interest.
humans would be obtained if investigations were made at
several time points during energy restriction, as opposed Received July 11, 2013; accepted July 23, 2013; previously published
to after a period of post-restriction re-feeding, as was the online August 21, 2013

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