Stress as a common risk factor for obesity and addiction (2014)

Biol Psychiatry. Author manuscript; available in PMC 2014 May 1.

Published in final edited form as:

PMCID: PMC3658316

NIHMSID: NIHMS461257

Rajita Sinha, PhDcorresponding author1,2,3 and Ania M. Jastreboff, MD, PhDcorresponding author4,5

The publisher’s final edited version of this article is available at Biol Psychiatry

See other articles in PMC that cite the published article.

 

Abstract

Stress is associated with obesity and the neurobiology of stress overlaps significantly with that of appetite and energy regulation. This review will discuss stress, allostasis, the neurobiology of stress and its overlap with neural regulation of appetite and energy homeostasis. Stress is a key risk factor in the development of addiction and in addiction relapse. High levels of stress changes eating patterns and augments consumption of highly palatable (HP) foods, which in turn, increases incentive salience of HP foods and allostatic load. The neurobiological mechanisms by which stress affects reward pathways to potentiate motivation and consumption of HP foods as well as addictive drugs is discussed. With enhanced incentive salience of HP foods and over-consumption of these foods, there are adaptations in stress and reward circuits that promote stress-related and HP food-related motivation as well as concomitant metabolic adaptations, including alterations in glucose metabolism, insulin sensitivity, and other hormones related to energy homeostatsis. These metabolic changes in turn may also affect dopaminergic activity to influence food motivation and intake of HP foods. An integrative heuristic model is proposed wherein repeated high levels of stress alter the biology of stress and appetite/energy regulation, with both components directly affecting neural mechanisms contributing to stress-induced and food cue-induced HP food motivation and engagement in overeating of such foods to enhance risk of weight gain and obesity. Future directions in research are identified to increase understanding of the mechanisms by which stress may increase risk of weight gain and obesity.

Keywords: Obesity, Stress, Addiction, Metabolism, Neuroendocrine, Reward

Obesity and addiction: the integral role of stress

Addiction to alcohol and drugs continues to be a significant public health problem with devastating medical, social and societal consequences (). Stress is a critical risk factor affecting both the development of addictive disorders and relapse to addictive behaviors, hence jeopardizing the course and recovery from these illnesses ().Obesity is a global epidemic, and the United States is at the forefront of the pandemic with two-thirds of its population classified as overweight or obese (BMI > 25kg/m2) (). The development of both obesity and addiction involves genetic, environmental and individual lifestyle characteristics that all contribute to this pandemic (); (). While previous reviews focus on these factors, this paper explores the role of stress, food cues and food motivation in contributing to overeating in obesity.

Stress and allostasis

Most simply, stress is the process by which any highly challenging, uncontrollable and overwhelming emotional or physiological event or series of events result in adaptive or maladaptive processes required to regain homeostasis and/or stability (), (). Examples of emotional stressors include interpersonal conflict, loss of a meaningful relationship, unemployment, death of a close family member, or loss of a child. Some common physiological stressors include hunger or food deprivation, insomnia or sleep deprivation, severe illness, extreme hyperthermia or hypothermia, psychoactive drug effects and drug withdrawal states. Stress-related adaptation involves the concept of allostasis, which is the ability to achieve physiological stability through change in internal milieu and to maintain apparent stability at a new physiological set point (); ()). According to McEwen and colleagues, there are ongoing adjustments of internal milieu, with fluctuations in physiology, mood, and activity as individuals respond and adapt to environmental demands (). Excessive stress to the organism, termed as increased allostatic load, results in “wear and tear” of the adaptive regulatory systems resulting in biological alterations that weaken stress adaptive processes and increase disease susceptibility (). Thus, high levels of uncontrollable stress and conditions of repeated and chronic stress promote sustained allostatic load resulting in dysregulated neural, metabolic and biobehavioral states that contribute to maladaptive behaviors and physiology outside of the homeostatic range {McEwen, 2007 #4}.

Stress, chronic adversity, and increased vulnerability to obesity

Similar to the effects of repeated and chronic stress on increasing addiction vulnerability (), considerable evidence from population-based and clinical studies indicates a significant and positive association of high uncontrollable stressful events and chronic stress states with adiposity, BMI and weight gain (), (), (), (). This relationship also appears to be strongest among individuals who are overweight and those who binge eat (), (), (). Using a comprehensive interview assessment of cumulative and repeated stress in a community sample of healthy adults (n=588), we found that higher numbers of stressful events and chronic stressors (see Table 1) over the lifetime was associated with excessive alcohol use, being a smoker and a higher BMI, after controlling for age, race, gender and socioeconomic status variables (see Figure 1).

Figure 1 

Total stress scores for cumulative adverse life events and chronic stress associated with (a) current smoking status (X2 = 31.66, df=1, P < 0.0001; Odds Ratio =1.196 {95%CI: 1.124–1.273}); (b) current alcohol use as categorized by NIAAA
Table 1 

List of Cumulative Stressful Events and Perceived Chronic Stressors Assessed in the Cumulative Adversitv Interview*

As stress affects weight gain and BMI, we also assessed its effects on basal glucose, insulin and insulin resistance. Morning screening of fasting plasma glucose (FPG) and insulin was assessed in a large subgroup of these healthy community volunteers and homeostasis model assessment (HOMA-IR) was calculated as an index of insulin resistance. We found that cumulative stress was associated with BMI-related changes in higher levels of glucose, insulin and HOMA-IR (Figure 2). These data indicate stronger associations between cumulative total stress and metabolic dysfunction among individuals in higher compared to lower BMI categories. These findings are similar to previous research indicating stronger effects of stress on increased substance use in individuals who are regular to heavy as compared to light or recreational users (). Together, these findings suggest that cumulative and repeated stress increases obesity risk and that individuals with higher BMIs may be more vulnerable to stress-related food consumption and subsequent weight gain.

Figure 2 

Greater total cumulative stress significantly predicts log transformed (a) fasting plasma glucose levels (adjusted R2 = 0.0189; t=2.88. p<.004), (b) fasting insulin (adjusted R2 = 0.016; t=2.74, p<.007), and, (c) HOMA-IR (adjusted R2 =

Stress and eating behaviors

Acute stress significantly alters eating (); (); (). While some studies show decreases in food intake under acute stress, acute stress can also increase intake, especially when HP, calorie-dense foods are available (, ), (), (), (). For example, by self-report alone, 42% of students reported increase food intake with perceived stress, and 73% of the participants reported increase in snacking during stress (). One third to half of animal or human laboratory studies show increases in food intake during acute stress, while others show no change or reduce intake (), (). Thus, while increased food intake with acute stress does not occur in everyone, certainly it does affect many individuals. Additionally, it is important to note that a number of experimental factors may contribute to research on these differential effects on acute stress-induced eating (), (), (). These factors include the specific type of stressor used in the manipulation, length of stress provocation, length of time of exposure to food intake and the amount and type of foods offered in the experiment, as well as the satiety and hunger level at the start of the study. These factors may contribute to the variability in results of the laboratory experiments that model stress effects on food intake.

There is significant evidence suggesting potentially detrimental effects of stress on eating patterns (e.g., skipping meals, restraining intake, binging) and food preference (). Stress can increase consumption of fast food (), snacks (), calorie-dense and highly-palatable foods (), and stress has been associated with increased binge eating (). The effects of stress may be different in lean as compared to obese individuals (, ). Stress-driven eating has been found to be exacerbated in obese women whereas stress-driven eating appears to have an inconsistent effect on food consumption in lean individuals (). Furthermore, changes in eating patterns may relate to carbohydrate metabolism and insulin sensitivity (). In healthy lean women, binge eating increases fasting glucose, insulin response, and alters the diurnal pattern of leptin secretion (). Irregular meal frequency has been found to increase insulin in response to a test meal after a period of irregular eating patterns (). Taken together, this research suggests that stress may promote irregular eating patterns and alter food preference and that overweight and obese individuals may be more vulnerable to such effects, possibly via weight-related adaptations in energy regulation and homeostasis.

The overlapping neurobiology of stress and energy homeostasis

The physiological responses to acute stress are manifested through two interacting stress pathways. The first is the hypothalamic-pituitary-adrenal (HPA) axis, in which corticotropin-releasing factor (CRF) is released from the paraventricular nucleus (PVN) of the hypothalamus, stimulating secretion of adrenocorticotrophin hormone (ACTH) from the anterior pituitary, which subsequently stimulates the secretion of glucocorticoids (GC) (cortisol or corticosterone) from the adrenal glands. The second is the autonomic nervous system, which is coordinated by the sympathoadrenal medullary (SAM) and the parasympathetic systems. Both components of these stress pathways also influence inflammatory cytokines and immunity (); ().

The release of CRF and ACTH from the hypothalamus and the anterior pituitary during stress results in GC release from the adrenal cortex, which in turn, supports energy mobilization and gluconeogenesis. Stress-related sympathetic arousal increases blood pressure and a diversion of blood flow from the gastrointestinal tract to skeletal muscles and the brain. The acute effects of stress on CRF and ACTH is terminated by GC negative feedback, supporting a return to homeostasis, and under such acute stress conditions, there is significant evidence that there is a decrease, rather than an increase, in food intake (), (). The hypothalamus is responsive to GCs via negative feedback, but also to insulin, secreted from the pancreas and integral to glucose metabolism and energy storage (), (), and to other hormones, like leptin which inhibits appetite, and ghrelin which promotes appetite (); (); Currie, 2005). Glucocorticoids increase plasma leptin and ghrelin levels, and ghrelin also increases with stress and is involved in regulating anxiety and mood (). Furthermore, a number of hypothalamic neuropeptides, such as CRF, propriomelanocortin (POMC), the orexigenic neuropeptide Y (NPY), and agouti-related peptide (AgRP), as well as the melanocortin receptors involved in regulating the stress response, also play a role in feeding (). Glucocorticoids alter the expression of these neuropeptides that regulate energy intake (), (). For example, bilateral adrenalecomy reduces food intake, and GC administration increases food intake by stimulating the release of NPY and inhibiting CRF release (). Furthermore, food restriction and high fat diets alter HPAaxis responses to stress and GC gene expression in a number of brain regions involved in energy homeostasis and stress (), (), (), (), (). Thus, the hypothalamus is a critical region in the stress circuit as well as in the regulation of feeding and energy balance.

Chronic and high levels of repeated and uncontrollable stress results in dysregulation of the HPA axis, with changes in GC gene expression (), (), which in turn, also affect energy homeostasis and feeding behavior. Chronic activation of the HPA axis is known to alter glucose metabolism and promote insulin resistance, with changes in a number of appetite-related hormones (e.g. leptin, ghrelin) and feeding neuropeptides (e.g. NPY) (), (), (), (). Chronic stress persistently increases GCs, and promotes abdominal fat, which in the presence of insulin, decreases HPA axis activity (), () (). Basic science studies have shown that adrenal steroids increase glucose and insulin levels as well as selection and intake of high caloric foods (), (), (), (). Chronic high GCs and increases in insulin have synergistic effects on increasing HP food intake and abdominal fat deposition (), (); (). High levels of repeated stress also result in sympathetic overactivity, and stress-related increases in autonomic responses are related to insulin levels and insulin resistance in adolescents and adults ().

Stress effects on food reward, motivation and intake

The hypothalamic stress circuits are under the regulation of extrahypothalamic cortico-limbic pathways modulated by CRF, NPY and noradrenergic pathways. The stress response is initiated via the amygdala and stress regulation occurs via GC negative feedback to the hippocampus and medial prefrontal cortical (mPFC) regions (). The extrahypothalamic projections of CRF are involved in subjective and behavioral responses to stress, while release of orexigenic NPY during stress and increased NPY mRNA in the arcuate nucleus of the hypothalamus, amygdala and hippocampus, increases feeding, but also decrease anxiety and stress (). Stress and GCs potentiate dopaminergic transmission and impact reward seeking and intake in laboratory animals (), () (). Acute stress increases acquisition of food reward, intake of high fat diets (), (), and compulsive food seeking of HP foods (), and promotes reward dependent habits (). Stress also potentiates craving for desserts, snacks and higher HP food intake in satiated overweight individuals relative to lean individuals ().

Increased drug taking and high fat diets alter CRF, GC and noradrenergic activity to increase sensitization of reward pathways (including the ventral tegmental area [VTA], nucleus accumbens [NAc], dorsal striatum and the mPFC regions) which influences preference for addictive substances and HP foods and increases drug/food craving and intake (), (),(). More importantly, this motivational circuit overlaps with limbic/emotional regions (eg. the amygdala, hippocampus, and insula) that play a role in experiencing emotions and stress, and in learning and memory processes involved in negotiating behavioral and cognitive responses critical for adaptation and homeostasis (); (). For example, amygdala, hippocampus and insula play an important role in coding of reward, reward cue-based learning and memory for high emotional and reward cues and potentiating emotion and reward cue-based feeding (), (). On the other hand, the medial and lateral components of the prefrontal cortex (PFC) are involved in higher cognitive and executive control functions and also in regulating emotions, physiological responses, impulses, desires and craving (). High and repeated stress alters structural and functional responses in these prefrontal and limbic brain regions, providing some basis for the effects of chronic stress on cortico-limbic regions that modulate food reward and craving (); (). These findings are consistent with behavioral and clinical research indicating that stress or negative affect decrease emotional, visceral and behavioral control, increase impulsivity () which, in turn, is associated with greater engagement in alcohol, smoking, and other drug abuse as well as increased intake of HP foods (); (); (). With increasing focus on food addiction and how craving for sweets and fat may promote obesity (), it would be important to consider whether vulnerability to food addiction is also exacerbated by chronic stress.

Food cues, food reward, motivation and intake

Highly palatable food cues are ubiquitous in the current obesogenic environment. Exposure to these HP food cues may increase food intake and contribute to weight gain (). Such foods are rewarding, stimulate the brain reward pathways and, via learning/conditioning mechanisms, increase the likelihood of HP food seeking and consumption (), (), (). Animals and humans can become conditioned to seek out and consume these HP foods, particularly in the context of stimuli or ‘cues’ associated with HP foods in the environment (), (), (). Such increases in conditioning and related increases in intake of HP foods result in adaptations in neural reward/motivation pathways, which occur with increased salience of these HP foods, and in turn, result in greater ‘wanting’ and seeking of HP foods, similar to the incentive salience processes that occur with increasing alcohol and drug intake (). A plethora of animal research and growing human neuroimaging research now clearly shows the involvement of brain reward regions and increased dopaminergic transmission with HP food cue exposure, with concomitant increases in food craving and motivation (), (), (), and greater responsivity of brain reward regions and food craving among individuals with higher BMI (), (), (), ().

With greater consumption of HP foods, the concomitant changes in carbohydrate and fat metabolism, insulin sensitivity and appetite hormones that modify energy homeostasis also influence neural reward regions involved in increasing salience, wanting and motivation for food intake (), (), (), (), (), (), (). For example, in healthy individuals food-related rise in plasma glucose stimulates insulin secretion, enabling glucose uptake into peripheral tissues; interestingly central infusion of insulin has been shown to suppress appetite and feeding (); ();();();(). However, chronic high levels of peripheral insulin and insulin resistance, as is observed in many individuals with obesity, may promote food craving and intake as well as alter dopaminergic activity in reward regions such as the VTA, NAc and dorsal striatum (), (), (), (). Similarly, leptin and ghrelin influence dopaminergic transmission in brain reward regions and food seeking behavior in animals, and activate brain reward regions in humans (), (), (), (). Insulin resistance and T2DM are also associated with changes in the function of neural reward circuits and their response to food cues (), (), (). We recently showed increased limbic and striatal reactivity to stress and food cues in obese relative to lean individuals () (see Figure 3). Furthermore, higher activity in the insula and dorsal striatum correlated with higher insulin levels, insulin resistance and with food craving when participants were exposed to favorite food contexts (). Together, these findings support the notion that there may be parallel and related adaptations in metabolic and neural motivation circuits that closely interact to dynamically influence hunger, food choices and selection, motivation for HP foods and overeating of HP foods.

Figure 3 

Axial brain slices in the obese and lean groups of neural activation differences observed in contrasts comparing favorite-food cue vs. neutral-relaxing conditions (A) and stress versus neutral-relaxing conditions (B) (threshold of p<0.01, FWE

Increasing evidence suggests that hormones involved in appetite and energy homeostasis (e.g., leptin, ghrelin, insulin) may also play a role in craving, reward and compulsive seeking of alcohol and drugs ();(); (); (); ();(); () These associations have generated interest in exploring the idea of “addiction transfer”, or replacing one “addiction”, in this case certain foods, for another, such as alcohol or other substances (). For example, a recent study found alcohol use increased following rapid, significant weight loss as is seen in patients who undergo bariatric surgery (). Thus, future research on the potential cross-sensitization of food and addictive substances in vulnerable individuals may shed light on the mechanisms underlying these phenomena.

Weight and diet-related metabolic and stress adaptations: influences on food craving and intake

Increasing levels of weight above healthy lean levels and overeating of HP foods, result in changes in glucose metabolism, insulin sensitivity and in hormones, regulating appetite and energy homesostasis (), (), (). As indicated in the previous sections, these metabolic factors not only influence neural reward regions to impact motivation, but also affect hypothalamic circuits, interacting with the overlapping stress and energy regulation circuitry. Thus, it is not surprising that increased weight, insulin resistance and high fat diets are associated with blunted GC responses to stress challenges and altered autonomic and peripheral catecholamine responses (), (), () (). As noted previously, high levels of stress and glucocorticoids increase glucose and insulin levels and also promote insulin resistance. Similarly, chronic high levels of insulin have been shown to downregulate HPA axis responses and increase basal sympathetic tone (), (), (), (). Additionally, evidence indicates that stress affects glucose levels and variability in both patients with type 1 and 2 diabetes (), (), (), while ghrelin, which via signaling of reward pathways promotes appetite and feeding (), is also involved in stress-induced food reward and food seeking () (). Thus, weight-related metabolic shifts in set-points may increase allostatic load with increased autonomic basal tone and altered HPA axis activity (), (), (), ().

Consistent with this previous work showing BMI and stress adaptations affecting food reward and motivation, we recently showed that acute stress increases amygdala activity and blunted medial orbito-frontal cortex response to milkshake vs. tasteless receipt, but this effect was moderated by high cortisol levels and by high BMI respectively (). Using a hyperinsulinemic clamp, we also showed that mild hypoglycemia potentiated activation of brain reward and limbic regions (hypothalamus, striatum, amygdala, hippocampus and insula) preferentially to HP food cues, an effect that correlated with increasing cortisol levels, while it decreased medial prefrontal activation, an effect that correlated with lowered glucose levels (). As mild hypoglycemia may be considered a physiological stressor, our findings suggest that glucose utilization may occur differentially in the brain with increasing stress, with enhanced motivation and limbic signaling in the presence of food cues but decreased neural response in self-control and regulatory prefrontal regions. Furthermore, this neural pattern was more striking in healthy obese individuals suggesting that such adaptations occur with increasing weight, perhaps setting the course for weight-related metabolic, neural and stress-related adaptations that influence HP food motivation. This study combined with earlier cited evidence suggests an exquisitely orchestrated neuroendocrine-metabolic-reward axis which under normal healthy conditions, coordinates physiological and psychological aspects of feeding and energy homeostasis, but with increasing risk factors and adaptations in these pathways, the regulatory circuits in each of these systems may be “hijacked”, thus promoting increased HP food motivation and intake.

Summary and proposed model

The converging lines of evidence presented suggest that ubiquitous HP food cues and high levels of stress may alter eating behaviors and affect brain reward/motivation pathways involved in wanting and seeking HP foods. Such behavioral responses may further promote changes in weight and body fat mass. Growing evidence supports weight-related bio-behavioral adaptations in interacting metabolic, neuroendocrine and neural (cortico-limbic-striatal) pathways, to potentiate food craving and intake under conditions of HP foods and related cues and with stress. Thus, a heuristic model is proposed of how HP foods, food cues and stress exposure may alter metabolic, stress and reward-motivation pathways in the brain and body to promote HP food motivation and intake (see Figure 4). As described in previous sections, stress-responsive hormones (CRF, GCs) and metabolic factors (insulin, ghrelin, leptin) each influence brain dopaminergic transmission, and with weight-related adaptations (chronic changes), these factors may promote higher levels of HP food motivation and intake, via potentiation of brain reward activity. Thus, a sensitized feed-forward process may ensue in which weight-related adaptations in metabolic, neuroendocrine and cortico-limbic striatal pathways promote HP food motivation and intake in vulnerable individuals. Such a sensitized process with increased HP food motivation and intake, would in turn, also promote future weight gain, thereby potentiating the cycle of weight-related adaptations in stress and metabolic pathways, and increased sensitization of brain motivation pathways in the context of HP food cues or stress, to promote HP food motivation and intake. In addition to weight and BMI, individual differences in genetic and individual susceptibility to obesity, eating patterns, insulin resistance, chronic stress, and other psychological variables may further moderate this process.

Figure 4 

A heuristic model is proposed of how HP foods, food cues and stress exposure may increase subjective (emotions, hunger) and also activate metabolic, stress and motivation systems in the brain and body to promote HP food motivation and intake (A). Stress-responsive

Future directions

While there is growing scientific attention on the complex interactions between stress, energy balance, appetite regulation, and food reward and motivation and their effects on the obesity epidemic, there are significant gaps in our understanding of these relationships. A number of key questions remain unanswered. For example, it is not known how stress-related neuroendocrine changes in cortisol, ghrelin, insulin and leptin, influence HP food motivation and intake. If chronic stress downregulates the HPA axis responses, as shown in previous research, how do these changes influence food craving and intake? It would be beneficial to examine if weight-related changes in stress, neuroendocrine and metabolic responses alter HP food motivation and intake, and whether such changes predict future weight gain and obesity. Identifying specific biomarkers and developing quantifiable measures to assess biobehavioral adaptations associated with stress and food addiction could assist in guiding optimal clinical care as well as targeting specific vulnerable subgroups with novel public health interventions. Furthermore, evidence on neuromolecular changes that occur in stress and metabolic pathways as they pertain to high-fat diets, and chronic stress, and how they relate to food intake and weight gain, would be critical in understanding the role that stress and metabolic adaptations play in food motivation, overeating and weight gain.

There is also a paucity of data on mechanisms underlying failure to maintain weight loss or relapse to overeating HP foods and weight gain, and on which obesity treatments are most suitable for which subgroup of individuals. The addiction field provides important clues on the neurobiological adaptations that promote addiction relapse and treatment failure. As failure to maintain weight loss has been discussed in the context of relapse to maladaptive behaviors (, ), it is possible that similar mechanisms may be driving relapse to overeating of HP foods and weight gain, but specific studies on this topic are rare. There is also a dearth of information on metabolic adaptations and their related effects on reward and stress neurobiology which may occur with the variety of weight-loss interventions, including gradual weight loss, rapid weight loss via “crash diets”, or various bariatric surgery interventions. Additionally, a number of stress-related illnesses, such as mood and anxiety disorders, are associated with obesity and T2DM, and interestingly, medications for such conditions (i.e. certain antidepressants) increase the risk of weight gain, but there is little evidence to elucidate the underlying mechanisms for these phenomena. In the setting of T2DM, tight glycemic control with exogenous insulin therapy often promotes weight gain. As hyperinsulinemia, insulin resistance, or the long-term effects of insulin resistance may potentiate motivation-reward neural pathways and food craving in obese, insulin-resistant individuals, it would be beneficial to investigate therapeutic approaches that may be less likely to promote HP food craving and intake to diminish further weight gain in these susceptible individuals.

Finally, there are new advances in behavioral and pharmacologic management of obesity but it is unclear how they relate to normalizing stress, metabolic and reward disturbances in vulnerable obese individuals. For example, recent evidence suggests that weight maintenance is associated with low stress level and better ability to cope with stress (); (). As stress promotes food craving and binge eating, stress reduction interventions may be useful in effective weight management programs, and some pilot behavioral stress reduction studies in obesity and T2DM are showing positive effects on improving stress, food craving and physiologic function (, ). However, such research is in its infancy and requires greater attention in the future. Also, medications used to treat drug abuse are also being considered as potential interventions for weight loss (). Indeed, future research on increasing our understanding of the neuro-behavioral-metabolic mechanisms underlying stress, addiction and obesity would be of tremendous benefit in the development of novel therapies to attenuate HP food motivation, intake and weight gain.

Acknowledgments

This work was supported by NIDDK/NIH, 1K12DK094714-01, and the NIH Roadmap for Medical Research Common Fund Grants UL1-DE019586, UL1-RR024139 (Yale CTSA), and the PL1-DA024859.

Footnotes

 

Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

 

 

Financial Disclosures: Dr. Sinha is on the Scientific Advisory Board for Embera Neutotherapeutics. Ania Jastreboff assists ManPower who provides contractors for the Pfizer New Haven Clinical Research Unit.

 

References

1. McLellan AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. Jama. 2000;284:1689–1695. [PubMed]
2. Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105–130. [PMC free article] [PubMed]
3. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. Jama. 2010;303:235–241. [PubMed]
4. Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science. 1998;280:1371–1374. [PubMed]
5. Friedman JM. Obesity: Causes and control of excess body fat. Nature. 2009;459:340–342. [PubMed]
6. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873–904. [PubMed]
7. Seeman TE, Singer BH, Rowe JW, Horwitz RI, McEwen BS. Price of adaptation–allostatic load and its health consequences. MacArthur studies of successful aging. Arch Intern Med. 1997;157:2259–2268. [PubMed]
8. Block JP, He Y, Zaslavsky AM, Ding L, Ayanian JZ. Psychosocial stress and change in weight among US adults. Am J Epidemiol. 2009;170:181–192. [PMC free article] [PubMed]
9. Dallman MF, Pecoraro NC, la Fleur SE. Chronic stress and comfort foods: self-medication and abdominal obesity. Brain Behav Immun. 2005;19:275–280. [PubMed]
10. Torres SJ, Nowson CA. Relationship between stress, eating Behavior, and obesity. Nutrition. 2007;23:887–894. [PubMed]
11. Adam TC, Epel ES. Stress, eating and the reward system. Physiol Behav. 2007;91:449–458. [PubMed]
12. Gluck ME, Geliebter A, Hung J, Yahav E. Cortisol, hunger, and desire to binge eat following a cold stress test in obese women with binge eating disorder. Psychosom Med. 2004;66:876–881. [PubMed]
13. Dallman M, Pecoraro N, Akana S, la Fleur S, Gomez F, Houshyar H, et al. Chronic stress and obesity: a new view of “comfort food” Proc National Academy of Science. 2003;100:11696–11701. [PMC free article] [PubMed]
14. Tempel DL, McEwen BS, Leibowitz SF. Effects of adrenal steroid agonists on food intake and macronutrient selection. Physiol Behav. 1992;52:1161–1166. [PubMed]
15. Tataranni PA, Larson DE, Snitker S, Young JB, Flatt JP, Ravussin E. Effects of glucocorticoids on energy metabolism and food intake in humans. Am J Physiol. 1996;271:E317–E325. [PubMed]
16. Wilson ME, Fisher J, Fischer A, Lee V, Harris RB, Bartness TJ. Quantifying food intake in socially housed monkeys: social status effects on caloric consumption. Physiol Behav. 2008;94:586–594. [PMC free article] [PubMed]
17. Oliver G, Wardle J. Perceived effects of stress on food choice. Physiology and Behaviour. 1999;66:511–515. [PubMed]
18. Dallman MF. Stress-induced obesity and the emotional nervous system. Trends Endocrinol Metab. 2010;21:159–165. [PMC free article] [PubMed]
19. Marti O, Marti J, Armario A. Effects of chronic stress on food intake in rats: influence of stressor intensity and duration of daily exposure. Physiol Behav. 1994;55:747–753. [PubMed]
20. Appelhans BM, Pagoto SL, Peters EN, Spring BJ. HPA axis response to stress predicts short-term snack intake in obese women. Appetite. 2010;54:217–220. [PMC free article] [PubMed]
21. Steptoe A, Lipsey Z, Wardle J. Stress, hassles and variations in alcohol consumption, food choice and physical exercise: A diary study. Brit J Health Psych. 1998;3:51–63.
22. Oliver G, Wardle J. Perceived effects of stress on food choice. Physiol Behav. 1999;66:511–515. [PubMed]
23. Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to appetite in women: a laboratory study of stress-induced cortisol and eating Behavior. Psychoneuroendocrinology. 2001;26:37–49. [PubMed]
24. Laitinen J, Ek E, Sovio U. Stress-related eating and drinking Behavior and body mass index and predictors of this behavior. Prev Med. 2002;34:29–39. [PubMed]
25. Lemmens SG, Rutters F, Born JM, Westerterp-Plantenga MS. Stress augments food ‘wanting’ and energy intake in visceral overweight subjects in the absence of hunger. Physiol Behav. 2011;103:157–163. [PubMed]
26. Jastreboff AM, Potenza MN, Lacadie C, Hong KA, Sherwin RS, Sinha R. Body mass index, metabolic factors, and striatal activation during stressful and neutral-relaxing states: an FMRI study. Neuropsychopharmacology. 2011;36:627–637. [PMC free article] [PubMed]
27. Farshchi HR, Taylor MA, Macdonald IA. Regular meal frequency creates more appropriate insulin sensitivity and lipid profiles compared with irregular meal frequency in healthy lean women. Eur J Clin Nutr. 2004;58:1071–1077. [PubMed]
28. Taylor AE, Hubbard J, Anderson EJ. Impact of binge eating on metabolic and leptin dynamics in normal young women. J Clin Endocrinol Metab. 1999;84:428–434. [PubMed]
29. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D., Jr Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992;13:387–414. [PubMed]
30. Chuang JC, Zigman JM. Ghrelin’s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept. 2010 2010, pii: 460549. Epub 2010 Feb 14. [PMC free article] [PubMed]
31. Maniam J, Morris MJ. The link between stress and feeding behaviour. Neuropharmacology. 2012;63:97–110. [PubMed]
32. Hanson ES, Dallman MF. Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis. J Neuroendocrinol. 1995;7:273–279. [PubMed]
33. Tyrka AR, Walters OC, Price LH, Anderson GM, Carpenter LL. Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults. Horm Metab Res. 2012;44:543–549. [PMC free article] [PubMed]
34. Hillman JB, Dorn LD, Loucks TL, Berga SL. Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls. Metabolism. 2012;61:341–348. [PMC free article] [PubMed]
35. Guarnieri DJ, Brayton CE, Richards SM, Maldonado-Aviles J, Trinko JR, Nelson J, et al. Gene profiling reveals a role for stress hormones in the molecular and behavioral response to food restriction. Biol Psychiatry. 2012;71:358–365. [PMC free article] [PubMed]
36. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–445. [PubMed]
37. Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 1998;83:1853–1859. [PubMed]
38. Rebuffe-Scrive M, Walsh UA, McEwen B, Rodin J. Effect of chronic stress and exogenous glucocorticoids on regional fat distribution and metabolism. Physiol Behav. 1992;52:583–590. [PubMed]
39. Bjorntorp P. Metabolic abnormalities in visceral obesity. Ann Med. 1992;24:3–5. [PubMed]
40. Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med. 2007;13:803–811. [PubMed]
41. Chrousos GP. The stress response and immune function: clinical implications. The 1999 Novera H. Spector Lecture. Ann N Y Acad Sci. 2000;917:38–67. [PubMed]
42. Warne JP. Shaping the stress response: interplay of palatable food choices, glucocorticoids, insulin and abdominal obesity. Mol Cell Endocrinol. 2009;300:137–146. [PubMed]
43. Keltikangas-Jarvinen L, Ravaja N, Raikkonen K, Lyytinen H. Insulin resistance syndrome and autonomically mediated physiological responses to experimentally induced mental stress in adolescent boys. Metabolism. 1996;45:614–621. [PubMed]
44. Schwabe L, Wolf OT. Stress prompts habit Behavior in humans. J Neurosci. 2009;29:7191–7198. [PubMed]
45. Aston-Jones G, Kalivas PW. Brain norepinephrine rediscovered in addiction research. Biol Psychiatry. 2008;63:1005–1006. [PMC free article] [PubMed]
46. Cottone P, Sabino V, Roberto M, Bajo M, Pockros L, Frihauf JB, et al. CRF system recruitment mediates dark side of compulsive eating. Proc Natl Acad Sci U S A. 2009;106:20016–20020. [PMC free article] [PubMed]
47. Paulus MP. Decision-making dysfunctions in psychiatry–altered homeostatic processing? Science. 2007;318:602–606. [PubMed]
48. Holland PC, Petrovich GD, Gallagher M. The effects of amygdala lesions on conditioned stimulus-potentiated eating in rats. Physiol Behav. 2002;76:117–129. [PubMed]
49. Berthoud HR. The neurobiology of food intake in an obesogenic environment. Proc Nutr Soc. 2012:1–10. [PMC free article] [PubMed]
50. Arnsten A, Mazure CM, Sinha R. This is your brain in meltdown. Sci Am. 2012;306:48–53. [PMC free article] [PubMed]
51. Liston C, McEwen BS, Casey BJ. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Natl Acad Sci U S A. 2009;106:912–917. [PMC free article] [PubMed]
52. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–625. [PubMed]
53. Willner P, Benton D, Brown E, Cheeta S, Davies G, Morgan J, et al. “Depression” increases “craving” for sweet rewards in animal and human models of depression and craving. Psychopharmacology. 1998;136:272–283. [PubMed]
54. Roberts C. The effects of stress on food choice, mood and body weight in healthy women. Nutrition Bulletin: British Nutrition Foundation. 2008;33:33–39.
55. Avena NM, Rada P, Hoebel BG. Sugar and fat bingeing have notable differences in addictive-like Behavior. J Nutr. 2009;139:623–628. [PMC free article] [PubMed]
56. Weingarten HP. Conditioned cues elicit feeding in sated rats: a role for learning in meal initiation. Science. 1983;220:431–433. [PubMed]
57. Alsio J, Olszewski PK, Levine AS, Schioth HB. Feed-forward mechanisms: Addiction-like behavioral and molecular adaptations in overeating. Front Neuroendocrinol. 2012;33:127–139. [PubMed]
58. Lutter M, Nestler EJ. Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr. 2009;139:629–632. [PMC free article] [PubMed]
59. Coelho JS, Jansen A, Roefs A, Nederkoorn C. Eating behavior in response to food-cue exposure: examining the cue-reactivity and counteractive-control models. Psychol Addict Behav. 2009;23:131–139. [PubMed]
60. Robinson TE, Berridge KC. Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci. 2008;363:3137–3146. [PMC free article] [PubMed]
61. Small DM, Zatorre RJ, Dagher A, Evans AC, Jones-Gotman M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain. 2001;124:1720–1733. [PubMed]
62. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, et al. Brain dopamine and obesity. Lancet. 2001;357:354–357. [PubMed]
63. Kelley AE, Schiltz CA, Landry CF. Neural systems recruited by drug- and food-related cues: studies of gene activation in corticolimbic regions. Physiol Behav. 2005;86:11–14. [PubMed]
64. Stice E, Spoor S, Ng J, Zald DH. Relation of obesity to consummatory and anticipatory food reward. Physiol Behav. 2009;97:551–560. [PMC free article] [PubMed]
65. Saelens BE, Epstein LH. Reinforcing value of food in obese and non-obese women. Appetite. 1996;27:41–50. [PubMed]
66. Simansky KJ. NIH symposium series: ingestive mechanisms in obesity, substance abuse and mental disorders. Physiol Behav. 2005;86:1–4. [PubMed]
67. Tetley A, Brunstrom J, Griffiths P. Individual differences in food-cue reactivity. The role of BMI and everyday portion-size selections. Appetite. 2009;52:614–620. [PubMed]
68. Figlewicz DP, Sipols AJ. Energy regulatory signals and food reward. Pharmacol Biochem Behav. 2010;97:15–24. [PMC free article] [PubMed]
69. DiLeone RJ. The influence of leptin on the dopamine system and implications for ingestive Behavior. Int J Obes (Lond) 2009;33(Suppl 2):S25–S29. [PMC free article] [PubMed]
70. Farooqui AA. Lipid mediators in the neural cell nucleus: their metabolism, signaling, and association with neurological disorders. Neuroscientist. 2009;15:392–407. [PubMed]
71. Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive Behavior. Cell Metab. 2008;7:400–409. [PubMed]
72. Dossat AM, Lilly N, Kay K, Williams DL. Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J Neurosci. 2011;31:14453–14457. [PMC free article] [PubMed]
73. Chuang JC, Perello M, Sakata I, Osborne-Lawrence S, Savitt JM, Lutter M, et al. Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest. 2011;121:2684–2692. [PMC free article] [PubMed]
74. Schwartz MW, Woods SC, Porte D, Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661–671. [PubMed]
75. Woods SC, Lotter EC, McKay LD, Porte D., Jr Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503–505. [PubMed]
76. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–846. [PubMed]
77. Sherwin RS. Bringing light to the dark side of insulin: a journey across the blood-brain barrier. Diabetes. 2008;57:2259–2268. [PMC free article] [PubMed]
78. Konner AC, Hess S, Tovar S, Mesaros A, Sanchez-Lasheras C, Evers N, et al. Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. Cell Metab. 2011;13:720–728. [PubMed]
79. Anthony K, Reed LJ, Dunn JT, Bingham E, Hopkins D, Marsden PK, et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes. 2006;55:2986–2992. [PubMed]
80. Kullmann S, Heni M, Veit R, Ketterer C, Schick F, Haring HU, et al. The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum Brain Mapp. 2012;33:1052–1061. [PubMed]
81. Jastreboff AM, Sinha R, Lacadie C, Small DM, Sherwin RS, Potenza MN. Neural Correlates of Stress- and Food- Cue-Induced Food Craving In Obesity: Association with insulin levels. Diabetes care. 2012 [PMC free article] [PubMed]
82. Chechlacz M, Rotshtein P, Klamer S, Porubska K, Higgs S, Booth D, et al. Diabetes dietary management alters responses to food pictures in brain regions associated with motivation and emotion: a functional magnetic resonance imaging study. Diabetologia. 2009;52:524–533. [PubMed]
83. Odom J, Zalesin KC, Washington TL, Miller WW, Hakmeh B, Zaremba DL, et al. Behavioral predictors of weight regain after bariatric surgery. Obes Surg. 2010;20:349–356. [PubMed]
84. Suzuki J, Haimovici F, Chang G. Alcohol use disorders after bariatric surgery. Obes Surg. 2012;22:201–207. [PubMed]
85. Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci. 2007;30:367–398. [PubMed]
86. Tamashiro KL, Hegeman MA, Nguyen MM, Melhorn SJ, Ma LY, Woods SC, et al. Dynamic body weight and body composition changes in response to subordination stress. Physiol Behav. 2007;91:440–448. [PMC free article] [PubMed]
87. Greenfield JR, Campbell LV. Role of the autonomic nervous system and neuropeptides in the development of obesity in humans: targets for therapy? Curr Pharm Des. 2008;14:1815–1820. [PubMed]
88. Wiesli P, Schmid C, Kerwer O, Nigg-Koch C, Klaghofer R, Seifert B, et al. Acute psychological stress affects glucose concentrations in patients with type 1 diabetes following food intake but not in the fasting state. Diabetes care. 2005;28:1910–1915. [PubMed]
89. Hermanns N, Scheff C, Kulzer B, Weyers P, Pauli P, Kubiak T, et al. Association of glucose levels and glucose variability with mood in type 1 diabetic patients. Diabetologia. 2007;50:930–933. [PubMed]
90. Faulenbach M, Uthoff H, Schwegler K, Spinas GA, Schmid C, Wiesli P. Effect of psychological stress on glucose control in patients with Type 2 diabetes. Diabet Med. 2012;29:128–131. [PubMed]
91. van Dijk G, Buwalda B. Neurobiology of the metabolic syndrome: an allostatic perspective. Eur J Pharmacol. 2008;585:137–146. [PubMed]
92. Rudenga KJ, Sinha R, Small DM. Acute stress potentiates brain response to milkshake as a function of body weight and chronic stress. Int J Obes (Lond) 2012 [PMC free article] [PubMed]
93. Page KA, Seo D, Belfort-DeAguiar R, Lacadie C, Dzuira J, Naik S, et al. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest. 2011;121:4161–4169. [PMC free article] [PubMed]
94. Brandon TH, Vidrine JI, Litvin EB. Relapse and relapse prevention. Annu Rev Clin Psychol. 2007;3:257–284. [PubMed]
95. Sinha R. Stress and Addiction. In: Brownell KD, Gold M, editors. Food and Addiction: A Comprehensive Handbook. Oxford University Press; 2012. pp. 59–66.
96. Sarlio-Lahteenkorva S, Rissanen A, Kaprio J. A descriptive study of weight loss maintenance: 6 and 15 year follow-up of initially overweight adults. Int J Obes Relat Metab Disord. 2000;24:116–125. [PubMed]
97. Elfhag K, Rossner S. Who succeeds in maintaining weight loss? A conceptual review of factors associated with weight loss maintenance and weight regain. Obes Rev. 2005;6:67–85. [PubMed]
98. Elder C, Ritenbaugh C, Mist S, Aickin M, Schneider J, Zwickey H, et al. Randomized trial of two mind-body interventions for weight-loss maintenance. J Altern Complement Med. 2007;13:67–78. [PubMed]
99. van Son J, Nyklicek I, Pop VJ, Blonk MC, Erdtsieck RJ, Spooren PF, et al. The Effects of a Mindfulness-Based Intervention on Emotional Distress, Quality-of-Life, and HbA1c in Outpatients With Diabetes (DiaMind): A randomized controlled trial. Diabetes care. 2012 [PMC free article] [PubMed]
100. Avena NM, Bocarsly ME, Hoebel BG, Gold MS. Overlaps in the nosology of substance abuse and overeating: the translational implications of “food addiction” Curr Drug Abuse Rev. 2011;4:133–139. [PubMed]