Impact of Stress on Metabolism and Energy Balance

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Impact of stress on metabolism and energy balance

Cristina Rabasa and Suzanne L Dickson

The stress response mobilizes the body’s energy stores in order to stress response. The dorsal cap and submagnocellular

respond to a threatening situation. A striking observation is the part of the PVN send projections to the brainstem and

diversity of metabolic changes that can occur in response to spinal nuclei controlling sympathetic and parasympa-

stress. On one hand acute intense stress is commonly associated thetic activity. During stress, activation of the sympa-

with feeding suppression and reduced body weight gain. The thetic nervous system (SNS) stimulates epinephrine and

activation of the hypothalamic–pituitary–adrenal axis and the a smaller, although signiﬁcant norepinephrine release

release of corticotropin-releasing hormone (CRH) might partially from the adrenal medulla, as well as norepinephrine

explain the anorexigenic effects of acute stress. CRH can also release from the sympathetic nerve endings [1]. These

stimulate the sympathetic nervous system and catecholamine catecholamines stimulate a(1–2) and b(1–3) receptors

release, inducing hypophagia and weight loss, through their expressed in different central and peripheral targets to

effects on the liver and on white and brown adipose tissue. On the coordinate cardiovascular responses (e.g. cardiac output

other hand, chronic stress can lead to dietary over-consumption and respiration are accelerated), redirect blood ﬂow to

(especially palatable foods), increased visceral adiposity and arouse the brain and prepare the muscles and the heart

weight gain. These obesogenic effects of stress are mainly for a ‘ﬁght or ﬂight’ response. The parvocellular part of

explained by the chronic release of glucocorticoids and the PVN is the origin of neurons sending axons to the

neuropeptide Y. Stressful situations can activate all of these median eminence, where they release corticotropin re-

systems together, and the metabolic outcome of stress exposure leasing hormone (CRH) thereby activating the hypotha-

is determined by a host of intrinsic and external factors. If we are lamic–pituitary adrenal axis (HPA). CRH reaches the

to ﬁnd new ways to limit the development of stress-linked pituitary gland and stimulates the synthesis and release

cardiometabolic diseases, we need to discover why, in some of adrenocorticotropic hormone (ACTH). Circulating

circumstances, the pro-obesogenic effects of stress outweigh its ACTH acts on melanocortin 2 (MC-2) receptors in the

anorexigenic effects. The equilibrium between the different

zona fasciculata of the adrenal cortex, stimulating the

components of the stress response that accompany chronic

synthesis and release of glucocorticoids (cortisol in

stress situations could be crucial to understand and prevent the

humans and corticosterone in rodents). These act in

long-lasting adverse metabolic effects induced by stress.

several tissues through the mineralocorticoid and gluco-

Address corticoid receptors (MR and GR) and exert negative

Department of Physiology, Institute of Neuroscience and Physiology, feedback on the HPA axis suppressing the stress re-

The Sahlgrenska Academy at the University of Gothenburg, sponse [2].

Medicinaregatan 11, PO Box 434, SE-405 30 Gothenburg, Sweden

Collectively all of the stress-linked changes in the SNS

Corresponding author: Rabasa, Cristina ([email protected])

and HPA axes mobilize the body’s energy stores in order

to allow a rapid response that favors survival under acute

Current Opinion in Behavioral Sciences 2016, 9:71–77 threatening situations. However, modern life stressors

This review comes from a themed issue on Diet, behavior and brain are typically chronic, including ﬁnancial worries, work

function problems, family responsibilities or health concerns [3].

Edited by Dana M Small and Susanne E la Fleur In this context, the stress response is not beneﬁcial but

rather becomes harmful, predisposing individuals to

For a complete overview see the Issue and the Editorial

visceral obesity and cardiometabolic disease [4,5], a

Available online 7th February 2016

leading cause of death worldwide. Still, the effects of

http://dx.doi.org/10.1016/j.cobeha.2016.01.011

stress on body weight and food intake are controversial.

2352-1546/# 2016 The Authors. Published by Elsevier Ltd. This is an Although there is a ink between stress and changes in

open access article under the CC BY-NC-ND license (http://creative-

eating habits in both men and women [6], not everyone

commons.org/licenses/by-nc-nd/4.0/).

gains weight under stress: about 40% increase and 40%

decrease their food intake [7]. Many studies have con-

tributed to understand the individual differences be-

Relevance of the stress response and stress tween those that gain and those that lose weight [6,8–

hormones for energy balance 10]. However, other factors like the chronicity and

Stress is the response of an organism to factors actually or intensity of the stressors, factors that are difﬁcult to

symbolically endangering its integrity. Irrespective of manipulate in humans, can be of major importance and

the type of stress, information about the situation con- could help to understand the physiological and neuro-

verges on the paraventricular nucleus (PVN) of the biological mechanisms underpinning the metabolic re-

hypothalamus, a brain region crucially involved in the sponse to stress.

www.sciencedirect.com Current Opinion in Behavioral Sciences 2016, 9:71–77

72 Diet, behavior and brain function

Figure 1

In this review we attempt to untangle the complex

relationship between stress and food intake, which tends

to favor an anorexigenic response when the stress is acute Control - NS IMOch - NS CUS - NS

Control - IMOa IMOch - IMOa CUS - IMOa

and severe. We adopt the view that under chronic or 30

repeated stress, (neuro)physiological adaptations occur

that give way to an orexigenic response. We describe 20

some of the known mechanisms and signaling systems

and highlight the important role of CRH, glucocorticoids

and NPY. Given that a number of recent reviews describe

the interaction between obesity and stress, we limit this

Body weight change (g) PS1 PS2 PS3 PS4

review to speciﬁc, perhaps less understood aspects of this –10

relationship that include the interactions between the Days after the last stress exposure

anorexigenic and orexigenic effectors of the HPA and Current Opinion in Behavioral Sciences

SNS axes during the stress response.

Influence of prior chronic stress exposure on body weight change

Severe stress induces anorexia after an acute immobilization (IMO). Rats were exposed to 9 days of

The most commonly reported result in rodents is that handling (control), chronic unpredictable stress (CUS) or chronic

immobilization (IMOch). On day 10, half of the rats in each group were

stress reduces food intake and body weight in a manner

exposed to handling (non-stress condition; Control-NS, IMOch-NS and

that is directly related to the stress severity [11]. A single

CUS-NS), or acutely exposed to 1 h of IMO (control-IMOa, IMOch-

exposure to restraint [12] or immobilization [13] induces a IMOa and CUS-IMOa). Data are represented as means + S.E.M.

reduction in body weight that can persist >10 days, even (n = 6–9) of cumulative body weight changes, relative to the body

weight achieved before the acute IMO exposure (day 10). Only the

if the food intake is quickly normalized [12,13]. More-

rats exposed to stress for the first time (Control-IMOa) lose weight

over, these body weight-lowering effects can be extreme-

after IMO ( p < 0.001 vs Control-NS group), while rats with either

ly long lasting after repeated exposure to the stressor.

chronic IMO or CUS are protected from the body weight reduction

Strikingly, rats do not catch up to the weight of non-stress induced by IMO. PS indicates the day post-stress (Pastor-Ciurana

controls even by 80 days after 3 consecutive days of et al. [15 ]).

restraint [14]. Thus, after stress, rats appear to have a

capacity to defend a new lower set-point for energy

homeostasis despite returning to normal caloric intake potent anorexigenic effects [18,19]. Despite this, CRHR1

and so energy expenditure must also be adjusted. How- or CRHR2 knockout mice do not differ from wildtypes

ever, even although chronically stressed rats do not catch regarding their food intake and body weight under non-

up to the weight of control never-stressed rats, prelimi- stressed conditions, suggesting that CRH receptors are

nary observations from our group demonstrate that rats not needed for the basal regulation of these parameters

exposed to 1 h/day of forced swim lose weight only on the [20,21]. However, severe impairments in the HPA axis

ﬁrst days of stress exposure, but then start to gain weight response have been observed in CRHR1 knockout mice

afterwards. Interestingly, this chronic stress-linked exposed to restraint, social defeat or forced swim stress

weight gain occurs despite a reduction in food intake, [20,22] but only minor alterations in the CRHR2 knock-

suggesting that metabolic adaptations occur during stress out mice [20,23]. The lack of CRHR1 also protects

which increase caloric efﬁciency. Supportively, Pastor-Ciur- against stress-induced hypophagia [24]. Consistent with

ana et al. [15 ] demonstrated that prior chronic unpredict- this, delivery of a non-speciﬁc CRH antagonist into the

able or repeated stress experience protects rats from the third [25], but not in the lateral or the fourth ventricle

anorectic effects of a subsequent acute and intense [25,26] prevents the weight loss induced by stress, impli-

stressor like immobilization (Figure 1). Therefore, al- cating the hypothalamus as the likely target for this effect.

though intense stress seems to induce immediate body Indeed, this lends support to the hypothesis that the

weight loss, compensatory mechanisms exist that restore effects of stress on weight loss involve CRH release

energy balance. within the PVN and the inhibition of NPY-neurons

[27]. However, infusions of CRHR2 antagonists in the

Short-term anorexia: a role for CRH and Urocortins bed nucleus of the stria terminalis (BNST) and lateral

The CRH system initiates the HPA axis response to stress septum (LS) [28] or CRHR1 antagonists to the basolateral

and it has been extensively linked to stress-induced amygdala (BLA) [29] can also prevent stress-induced

anorexia. CRH and its analogs Urocortins (UCN) 1–3 anorexia. It should be noted, however, that these beneﬁ-

act as neurotransmitters and activate CRHR1 and cial effects of the CRH antagonists are rather mild and

CRHR2 receptors that have a role in food intake, weight short lived in the stress condition [30]; most studies report

gain and metabolic control [16 ,17]. Under basal condi- effects at 1-hour post stress in food-deprived rats [31,32].

tions, peripheral and i.c.v. injections of CRH or Urocor- Future studies should aim to follow the effects of these

tins decrease food intake and body weight gain for up to CRH receptor antagonist drugs for a longer period after

48 hours after injection, with Ucn1 having the most the stress.

Current Opinion in Behavioral Sciences 2016, 9:71–77 www.sciencedirect.com

Stress and metabolism Rabasa and Dickson 73

Body weight reduction and energetic status forced swim induce very strong stress responses, and it is

It is widely accepted that manipulations causing in- possible that these rodent stressors are modeling a se-

creased sympathetic tone (such as that induced by stress) verely traumatic situation. In addition, when these stress-

are linked to increased thermogenesis in brown adipose ors are repeatedly presented, rodents adapt very fast [50].

tissue (BAT), decreased food intake and body weight Human studies typically involve milder but chronic

[33]. Catecholamines stimulate lipolysis and the release stressors [3], and they demonstrate that stress can increase

of fatty acids from the adipose tissue, and also glycogen- body weight and preference for palatable food in many

olysis and gluconeogenesis in the liver [34,35]. CRH and ways [9,10,51,52]. Stress engages pathways that confer the

ACTH contribute to stimulate the SNS and the noradren- reward value of foods, such as the mesocorticolimbic

aline release [36,37], and extrahypothalamic brain areas dopamine pathway. By activating this pathway, glucocor-

containing CRH immunoreactive neurons, like BNST ticoids increase motivating aspects of drugs [53], and

and central amygdala, participate through the simulation potentially also for palatable food. In this regard, the

of the locus coeruleus (LC) [38]. Energy expenditure ‘Comfort Food’ hypothesis proposed by Dallman [54]

increases while the respiratory quotient decreases during suggests that eating palatable high fat/sugar food can

restraint or chronic mild stress [14,39]. This increase in relieve negative emotions linked to stress and reduce

energy expenditure is coupled to an increase in body and the HPA axis response [52,54,55]. Firstly, it was sug-

BAT temperature under stress in rodents [36,40,41], gested that the visceral fat might act as a signal of energy

mediated by the glutamatergic stimulation of the dor- stores that feeds back to inhibit the HPA axis [54,56 ],

somedial hypothalamus to the rostral medullary raphe but this hypothesis has been updated. Using a model of

region (rMR) that participates in the sympathetic stimu- limited access to sucrose, which reduces the stress re-

lation of BAT [40]. Stress-linked hyperthermia can be sponse, Ulrich-Lai et al. [57 ] propose that sucrose intake

prevented with a receptor agonist of 5-HT1A in the rMR, alters signaling between the PVN and the basolateral/

by CRH antagonists delivery to the brain ventricles [36] medial amygdala on one side and the BNST on the other,

and also by antagonists to b-3 adrenoceptor highly resulting in a diminished response to stress.

expressed in BAT [40–42]. Indeed, stress hyperthermia

seems to be mediated by BAT thermogenesis. Moreover, Apart from increasing the motivation to eat palatable

acute and chronic immobilization increase UCP-1 activity food, increasing visceral obesity is one way in which

in BAT, and the effect is stronger after chronic stress [43]; chronic stress increases the risk of metabolic syndrome,

this ﬁts with the increased response of BAT thermogen- since abdominal obesity is one of its core symptoms

esis to norepinephrine after repeated stress [44]. On the (together with hypertension, high fasting glucose levels

other hand, GCs can oppose these effects; dexametha- and triglycerides and low HDL cholesterol levels), meta-

sone inhibits adrenergic stimulation of the functioning of bolic alterations strongly related with the development of

human brown adipocytes [45], and corticosterone attenu- type-2 diabetes and cardiovascular disease [58].

ates the stimulatory effects of ACTH and norepinephrine

on BAT (increase UCP1 expression) in vitro and in vivo in Acute and chronic effects of glucocorticoids

mice through the GR receptors [37]. Glucocorticoids (GC) have a complex role in energy

balance and metabolic control. Acutely, they are con-

The catabolic effects of SNS activation during stress are sidered catabolic hormones, that increase lipolysis and

not only observed in BAT but also in white adipose tissue the release of fatty acids from WAT [59], and stimulate

(WAT). In WAT, the release of catecholamines under hepatic glycogenolysis and gluconeogenesis, increasing

stress and the consequent stimulation of b adrenergic the circulating glucose concentrations and the glycogen

receptors increases lipolysis and inhibits the proliferation deposition [60]. However, an anabolic effect of GCs

of preadipocytes [46], while the lack of norepinephrine within WAT has been demonstrated [61 ]. People suf-

increases the fat cell number and the WAT mass [47]. In fering from Cushing syndrome, endogenous hypercor-

addition, repeated immobilization stimulates catechol- tisolism, have abdominal obesity, increased body fat,

amine biosynthesis in visceral WAT [48], and chronic high blood pressure, insulin resistance and preference

cold stress [49 ] or in vitro culture with ACTH [37] can for fat food [62,63]. It has been hypothesized that

change the WAT to BAT-like morphology, with high insulin, frequently released as a consequence of GC

expression levels of UCP-1 perhaps increasing thermo- action [64–66], might be crucial in food choice and fat

genesis. accumulation in stress [67]. In absence of insulin, GC

increase the intake of chow, rich in carbohydrates [65],

Chronic stress increases body weight and risk while in presence of insulin, GC increase the preference

for cardiometabolic disease for more palatable options [68,69]. However, when the

Whereas in rodents stress usually induces weight loss, in GC levels are constantly high as is the case of chronic

humans, this effect is not always observed, and depends stress, insulin resistance is observed. Thus, other

upon which experimental designs are used to explore the factors have to be responsible for the fat preference

stressor. In rodents, the classic stressors like restraint, or in the long term.

www.sciencedirect.com Current Opinion in Behavioral Sciences 2016, 9:71–77

74 Diet, behavior and brain function

Figure 2

Brain Food intake

Body weight PVN BNST Motivation to eat palatable food AMY Liver CRH Gluconeogenesis Glycogenolysis

BAT ACTH BAT induced

Sympathetic neuron thermogenesis Glucocorticoids Preadipocyte differentiation Stress hyperthermia

Epinephrine WAT Norepinephrine Lipolysis Preadipocyte NPY differentiation Adipocyte

proliferation Stimulation Inhibition

Current Opinion in Behavioral Sciences

The different systems involved in the stress effects on energy balance and their stimulatory and inhibitory role in different organs. PVN:

paraventricular nucleus of the hypothalamus; AMY: amygdale; BNST: bed nucleus of the stria terminalis; CRH: corticotropin-releasing hormone;

ACTH: adrenocorticotropic hormone; NPY: neuropeptide Y; BAT: brown adipose tissue; WAT: white adipose tissue.

Glucocorticoids also affect BAT, which is involved in of the SNS, from where it is released as an adrenergic

thermoregulation and energy expenditure. BAT-induced cotransmitter under some stress situations [73]. Centrally,

thermogenesis can contribute to a reduction in body fat NPY potently increases food intake through its effects in

[70]. GCs appear to be required for BAT cell differentia- the hypothalamus, that can be considered a ﬁght against

tion (in vitro) [45,71] yet in high concentrations, gluco- starvation under stress. Additionally, central NPY exerts

corticoids have been shown to impair BAT-induced protective effects under stress by reducing anxiety and

thermogenesis in vivo [72]. Consistent with this, GCs depressive-like behaviors [74] and can increase fat intake

inhibits the adrenergic stimulation of the functioning of when is infused in the Nucleus Accumbens [75]. Simulta-

the brown adipocytes in vitro [45,71]. Therefore, GCs neously, injections of a synthetic GC or one session of

may impact on energy balance through their actions in footshock increase NPY content in the ARC, and decrease

WAT and BAT. However, under stressful situations, the amount of CRH in the mediobasal hypothalamus

other factors like the activation of the SNS can oppose [64,76], both of which could contribute to a feeding re-

these effects, and the net result can depend on the sponse. Likewise, chronic restraint increases the expres-

combination of both systems. sion of the orexigenic peptide agouti-related peptide

(AgRP, which colocalises with NPY) in the lateral hypo-

Neuropeptide Y is engaged in the stress response at thalamus and down-regulates the melanocortin receptor 4

many levels (MC4) in ARC, that responds to the anorexigenic proo-

Another important peptide linking stress and adiposity is piomelanocortin (POMC) [77], potentiating orexigenic

neuropeptide Y (NPY), a peptide produced both in the systems. However, a parallel stimulation of anorexigenic

arcuate nucleus (ARC) of the hypothalamus and in neurons pathways has been also observed in the ARC, since acute

Current Opinion in Behavioral Sciences 2016, 9:71–77 www.sciencedirect.com

Stress and metabolism Rabasa and Dickson 75

footshock or restraint down-regulates AgRP [76,77], and different types of stress with food intake and energy

acute restraint increases the expression of POMC in the balance will facilitate the development of strategies that

whole hypothalamus [78]. circumvent the development of stress-linked metabolic

disease.

NPY can be released as an adrenergic cotransmitter,

acting by itself or modulating the effects of norepineph-

Conﬂict of interest statement

rine and ATP, also released from the sympathetic term-

Nothing declared.

inals. For example, in WAT, NPY appears to oppose the

effects of norepinephrine, inhibiting lipolysis induced by

Acknowledgements

a b-agonist in cultured adipocytes [79]. Kuo et al. [49 ]

We gratefully acknowledge support from the EC projects Nudge-it and

demonstrated that NPY is upregulated in WAT after

Full4Health (under grant agreement numbers 607310 and 266408

chronic cold and social defeat stress in mice fed the high respectively), from the Swedish Research Council for Medicine (2012-1758)

and from Forskning och Utveklingsarbete (ALFGBG-138741). Thanks to

fat-high sucrose diet. Besides, the increase in abdominal

Dr Erik Schele for his help with the design of the Figure 2, and to Prof

fat and the symptoms resembling metabolic syndrome in

John-Olov Jansson for reading and commenting on the text.

these mice were reversed by delivery of a NPY2R antag-

onist to the abdominal fat. They show that NPY increases

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