The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review

doi:10.1016/j.pnpbp.2021.110303

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 110, 30 August 2021, 110303

https://doi.org/10.1016/j.pnpbp.2021.110303 Get rights and content

Highlights

•
Compulsive overeating is commonly triggered by stress and negative mood.
•
GLP-1R are found in stress, emotion and reward regulatory areas in the brain.
•
GLP-1R agonists induce acute anxiogenic yet chronic anxiolytic states in rodents.
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Long-term GLP-1R agonist clinical trials measuring stress, mood and eating are needed.
•
Promising evidence for GLP-1R agonists for depression and drug addiction treatment.

Abstract

Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250)

Section snippets

Stress exacerbates compulsive overeating

Individuals with obesity commonly experience high levels of chronic stress (Foss and Dyrstad, 2011) and depression (Jantaratnotai et al., 2017), and can engage in hedonic overeating as a coping mechanism (Dallman et al., 2003). Whilst not all individuals with obesity exhibit hedonic overeating, obesity is highly comorbid with disordered eating (Giel et al., 2017), specifically binge eating (Razzoli et al., 2017), which is exacerbated by stress (Haedt-Matt and Keel, 2011) and other negative

Peripheral GLP-1

Processed from its precursor, proglucagon, in the gut, GLP-1 is an incretin hormone secreted postprandially in a biphasic manner by enteroendocrine L-cells primarily in response to carbohydrate ingestion (Lavin et al., 1998) to stimulate glucose-dependent insulin secretion (Ghosal et al., 2013).

Circulating GLP-1 is primarily found in two bioactive forms, GLP-1_7-36 amide and GLP-1_7-37 amide (Marks et al., 1991) and has a very short circulating half-life (<2 mins) due to rapid degradation by

Methods of review

An initial PubMed search for English-language published articles (no year limit) was done with key terms: “GLP or glucagon-like or exenatide or liraglutide or lixisenatide or albiglutide or dulaglutide or semaglutide or exendin AND stress or cortisol or corticosterone or glucocorticoid or ACTH or CRF or CRH or mood or anxiety or depression or emotion” on 13^th December 2018. The search yielded 1,931 results. Titles and abstracts were screened, resulting in 45 relevant papers.

A follow up search

In-vitro studies

Acute administration of GLP-1 in vitro (Table 2) in rat adrenocortical cells leads to a dose-dependent increase in corticosterone compared to saline (Malendowicz et al., 2003a), but no change compared to glucagon (Andreis et al., 1999). An in vitro study measuring CRF mRNA expression in hypothalamic PVN 4B cells also showed an increased expression as a result of GLP-1 administration (two-fold compared to baseline) when administered GLP-1 acutely in a dose-dependent manner (Kageyama et al., 2012

Discussion

Overall, the pre-clinical literature points to potential diverging effects of GLP-1 depending on length of exposure: a stress-inducing effect (or no effect) when administered acutely, yet an anxiolytic and anti-depressive effect chronically (see Table 3). Discrepancies between study results at a pre-clinical level may be explained by differences in strain of rats or mice which notoriously have varying levels of stress-profiles, tasks used (e.g., elevated plus maze vs. light/dark box),

Therapeutic value for compulsive/stress-related eating

The therapeutic value of GLP-1 agonists to reduce response to craving of rewarding substances needs to consider the observed acute stress-reactive, HPA-stimulating effects of GLP-1 and GLP-1 analogues as seen in pre-clinical studies. This is particularly relevant for stress-vulnerable groups. Longitudinal data on GLP-1 and addictive-like behaviors in humans is minimal, therefore future work should investigate how GLP-1 analogues may be affecting stress-vulnerable groups (such as people with

Conclusion

There is an increasing understanding that the hedonic drive for eating is a valuable therapeutic target behavior for people with obesity. This type of eating behavior is often triggered by feelings of stress and negative mood states. The central role of GLP-1 in suppressing appetite and altering the rewarding value of high-energy dense food is also mirrored by a potential alteration of stress-regulatory areas of the brain such as the hypothalamus. Hence, this review provides an overview of the

Declaration of Competing Interest

P.S. reports fees from Novo Nordisk for participation in advisory boards and a lecture unrelated to the submitted work.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

EGH is supported by a Melbourne Research Scholarship. APG is supported by UK Medical Research Council Experimental Medicine Grant (MR/M007022/1). RMB is supported by ARC DECRA (DE190101244). PS is supported by a National Health and Medical Research Council Investigator Grant (1178482).

References (197)

M. Al’Absi
Hypothalamic–pituitary–adrenocortical responses to psychological stress and risk for smoking relapse
Int. J. Psychophysiol.
(2006)
R.H. Anderberg et al.
GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality
Psychoneuroendocrinology
(2016)
P.G. Andreis et al.
Effects of glucagon and glucagon-like peptide-1 on glucocorticoid secretion of dispersed rat adrenocortical cells
Life Sci.
(1999)
S. Baboumian et al.
Functional Magnetic Resonance Imaging (fMRI) of neural responses to visual and auditory food stimuli pre and post Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG)
Neuroscience
(2019)
S.C. Cork et al.
Distribution and characterisation of glucagon-like peptide-1 receptor expressing cells in the mouse brain
Mol. Metab.
(2015)
P. Cottone et al.
Consummatory, anxiety-related and metabolic adaptations in female rats with alternating access to preferred food
Psychoneuroendocrinology
(2009)
M.F. Dallman
Stress-induced obesity and the emotional nervous system
Trends Endocrinol. Metab.
(2010)
A. De Silva et al.
The gut hormones PYY3-36 and GLP-17-36 amide reduce food intake and modulate brain activity in appetite centers in humans
Cell Metab.
(2011)
J. Dean et al.
The neurobiology of depression: an integrated view
Asian J. Psychiatr.
(2017)
L. Décarie-Spain et al.
GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice
Neuropharmacology
(2019)

K. Erreger et al.

Exendin-4 decreases amphetamine-induced locomotor activity

Physiol. Behav.

(2012)

B. Foss et al.

Stress in obesity: cause or consequence?

Med. Hypotheses

(2011)

S. Ghosal et al.

Role of central glucagon-like peptide-1 in stress regulation

Physiol. Behav.

(2013)

P. Grant et al.

Psychological and quality of life changes in patients using GLP-1 analogues

J. Diabetes Complicat.

(2011)

R.B. Grigolon et al.

Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

(2019)

G. Gulec et al.

Effects of centrally-injected glucagon-like peptide-1 on pilocarpine-induced seizures, anxiety and locomotor and exploratory activity in rat

Neuropeptides

(2010)

M.R. Hayes et al.

Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation

Cell Metab.

(2011)

J.P. Herman et al.

Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis

Trends Neurosci.

(1997)

J.P. Herman et al.

Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

(2005)

N.S. Hernandez et al.

Central GLP-1 receptors: novel molecular targets for cocaine use disorder

Physiol. Behav.

(2019)

J.J. Holst et al.

Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss

Surg. Obes. Relat. Dis.

(2018)

R. Isacson et al.

The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test

Eur. J. Pharmacol.

(2011)

N. Jantaratnotai et al.

The interface of depression and obesity

Obes. Res. Clin. Pract.

(2017)

E. Jerlhag

GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence

Neuropharmacology

(2018)

K. Kageyama et al.

Dexamethasone stimulates the expression of ghrelin and its receptor in rat hypothalamic 4B cells

Regul. Pept.

(2012)

M. Kamble et al.

Neurobehavioral effects of liraglutide and sitagliptin in experimental models

Eur. J. Pharmacol.

(2016)

S. Kamei et al.

Increase in cortisol/ACTH ratio after chronic treatment with liraglutide in patients with type 2 diabetes

Diabetes Metab.

(2017)

J. Kandiah et al.

Stress influences appetite and comfort food preferences in college women

Nutr. Res.

(2006)

K. Katsurada et al.

Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: Projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons

Biochem. Biophys. Res. Commun.

(2014)

W. Kaye

Neurobiology of anorexia and bulimia nervosa

Physiol. Behav.

(2008)

B. Kreymann et al.

Glucagon-like peptide-1 7-36: a physiological incretin in man

Lancet

(1987)

J.H. Lavin et al.

Interaction of insulin, glucagon-like peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate

Am. J. Clin. Nutr.

(1998)

Amber Alhadeff et al.

Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

American Journal of Physiology: Regulatory, Integrative and Comparative Physiology

(2014)

A.L. Alhadeff et al.

GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake

Endocrinology

(2012)

E. Alvarez et al.

The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem

J. Neurochem.

(2005)

R.G. Anversa et al.

A model of emotional stress-induced binge eating in female mice with no history of food restriction

Genes Brain Behav.

(2020)

P. Behary et al.

Food preferences and underlying mechanisms after bariatric surgery

Proc. Nutr. Soc.

(2015)

H.-R. Berthoud

The neurobiology of food intake in an obesogenic environment

Proc. Nutr. Soc.

(2012)

J.H. Best et al.

Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily1

Diabet. Med.

(2009)

J.H. Best et al.

Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment

Diabetes Care

(2011)

B.W. Bode et al.

Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes

Diabetes Obes. Metab.

(2010)

T. Burrows et al.

Food addiction and associations with mental health symptoms: a systematic review with meta-analysis

J. Hum. Nutr. Diet.

(2018)

J. Cegla et al.

Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake

Diabetes

(2014)

I.K. Celikyurt et al.

Exenatide treatment exerts anxiolytic- and antidepressant-like effects and reverses neuropathy in a mouse model of type-2 diabetes

Med. Sci. Monit. Basic Res.

(2014)

N. Chhina et al.

Healthier Food Hedonics and Emotional Eating Link With Orbitofrontal Cortex and Amygdala Responses to Food and Unpleasant Images After Gastric Bypass Surgery

(2016)

K.G. Commons et al.

The rodent forced swim test measures stress-coping strategy, not depression-like behavior

ACS Chem. Neurosci.

(2017)

K.P. Cosgrove et al.

Opposing relationships of BMI with BOLD and dopamine D2/3 receptor binding potential in the dorsal striatum

Synapse

(2015)

P. Cottone et al.

Intermittent access to preferred food reduces the reinforcing efficacy of chow in rats

Am. J. Phys. Regul. Integr. Comp. Phys.

(2008)

P. Cottone et al.

CRF system recruitment mediates dark side of compulsive eating

Proc. Natl. Acad. Sci.

(2009)

M.F. Dallman et al.

Chronic stress and obesity: a new view of “comfort food”

Proc. Natl. Acad. Sci. U. S. A.

(2003)

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Actually, the effects of stress on food intake have an anorexigenic effect on animals, since avoiding food-seeking actions might be protective when there is a potential threat. However, in these situations there is an increasing preference for the consumption of energy-dense foods to compensate this reduction in seeking behavior [21,22]. In humans, approximately 40% will increase their appetite in acute stress situations and 40% will reduce it [23].
Emotional eating (EE) and other abnormal eating patterns are highly prevalent among people living with obesity (PWO). In this sense, semaglutide, by acting on areas of the brain involved in the reward system and emotion regulation, could have the potential to ameliorate these eating patterns.
69 PWO attending an obesity clinic were evaluated baseline and after 3 months since the beginning of semaglutide. To rule out abnormal EE, the Emotional Eating Questionnaire was administered, and a structured interview was conducted. Results: 69 PWO (82.6%♀, 43.7 ± 1years, and 34.3 ± 6 kg/m²) were included. After 3 months of semaglutide, there was a significant reduction in weight (96.1 ± 20.9 vs 91.3 ± 19.7 kg; p < 0.001) and BMI (34.3 ± 6 vs 32.4 ± 5.6 kg/m²; p < 0.0001). The proportion of patients with EE (72.5% vs 11.5%; p < 0.001), external eating (27.5% vs 10.1%; p < 0.001) cravings (49.3% vs 21.7%; p < 0.001) and savory cravings (53.6% vs 14.5%; p < 0.001) was significantly reduced after 3 months of semaglutide. Also, the proportion of PWO with regular exercise was increased (15.9% vs 39.1%; p < 0.001). However, Logistic regression analysis showed that only sweet cravings at baseline were the only factor associated, although not significant, with a poorer weight loss (p = 0.05).
Semaglutide is an effective weight-loss treatment in PWO at short term. Moreover, semaglutide was highly effective in ameliorating EE and other abnormal eating patterns that exert a negative influence on weight.
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The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review

Highlights

Abstract

Section snippets

Stress exacerbates compulsive overeating

Peripheral GLP-1

Methods of review

In-vitro studies

Discussion

Therapeutic value for compulsive/stress-related eating

Conclusion

Declaration of Competing Interest

Acknowledgements

Int. J. Psychophysiol.

Psychoneuroendocrinology

Life Sci.

Neuroscience

Mol. Metab.

Psychoneuroendocrinology

Trends Endocrinol. Metab.

Cell Metab.

Asian J. Psychiatr.

Neuropharmacology

Physiol. Behav.

Med. Hypotheses

Physiol. Behav.

J. Diabetes Complicat.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Neuropeptides

Cell Metab.

Trends Neurosci.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Physiol. Behav.

Surg. Obes. Relat. Dis.

Eur. J. Pharmacol.

Obes. Res. Clin. Pract.

Neuropharmacology

Regul. Pept.

Eur. J. Pharmacol.

Diabetes Metab.

Nutr. Res.

Biochem. Biophys. Res. Commun.

Physiol. Behav.

Lancet

Am. J. Clin. Nutr.

Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

American Journal of Physiology: Regulatory, Integrative and Comparative Physiology

GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake

Endocrinology

The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem

J. Neurochem.

A model of emotional stress-induced binge eating in female mice with no history of food restriction

Genes Brain Behav.

Food preferences and underlying mechanisms after bariatric surgery

Proc. Nutr. Soc.

The neurobiology of food intake in an obesogenic environment

Proc. Nutr. Soc.

Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily1

Diabet. Med.

Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment

Diabetes Care

Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes

Diabetes Obes. Metab.

Food addiction and associations with mental health symptoms: a systematic review with meta-analysis

J. Hum. Nutr. Diet.

Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake

Diabetes

Exenatide treatment exerts anxiolytic- and antidepressant-like effects and reverses neuropathy in a mouse model of type-2 diabetes

Med. Sci. Monit. Basic Res.

Healthier Food Hedonics and Emotional Eating Link With Orbitofrontal Cortex and Amygdala Responses to Food and Unpleasant Images After Gastric Bypass Surgery

The rodent forced swim test measures stress-coping strategy, not depression-like behavior

ACS Chem. Neurosci.

Opposing relationships of BMI with BOLD and dopamine D2/3 receptor binding potential in the dorsal striatum

Synapse

Intermittent access to preferred food reduces the reinforcing efficacy of chow in rats

Am. J. Phys. Regul. Integr. Comp. Phys.

CRF system recruitment mediates dark side of compulsive eating

Proc. Natl. Acad. Sci.

Chronic stress and obesity: a new view of “comfort food”

Proc. Natl. Acad. Sci. U. S. A.