The menace of obesity to depression and anxiety prevalence

Obesity increases the incidence of depression and anxiety as a function of the extent of metabolic dysfunction.Diets that include excess saturated fat and sugar intake promote metabolic dysfunction, neuroinflammation, and mental health impairments.Adipose- and gut-derived inflammation and changes in brain nutrient composition stimulate neuroinflammation.Neuroinflammation alters structure, excitability, and connectivity in corticolimbic networks controlling mood, motivation, and emotion. The incidence of depression and anxiety is amplified by obesity. Mounting evidence reveals that the psychiatric consequences of obesity stem from poor diet, inactivity, and visceral adipose accumulation. Resulting metabolic and vascular dysfunction, including inflammation, insulin and leptin resistance, and hypertension, have emerged as key risks to depression and anxiety development. Recent research advancements are exposing the important contribution of these different corollaries of obesity and their impact on neuroimmune status and the neural circuits controlling mood and emotional states. Along these lines, this review connects the clinical manifestations of depression and anxiety in obesity to our current understanding of the origins and biology of immunometabolic threats to central nervous system function and behavior. The incidence of depression and anxiety is amplified by obesity. Mounting evidence reveals that the psychiatric consequences of obesity stem from poor diet, inactivity, and visceral adipose accumulation. Resulting metabolic and vascular dysfunction, including inflammation, insulin and leptin resistance, and hypertension, have emerged as key risks to depression and anxiety development. Recent research advancements are exposing the important contribution of these different corollaries of obesity and their impact on neuroimmune status and the neural circuits controlling mood and emotional states. Along these lines, this review connects the clinical manifestations of depression and anxiety in obesity to our current understanding of the origins and biology of immunometabolic threats to central nervous system function and behavior. The peril of mood and anxiety disorders is receiving increasing attention beyond psychiatric and psychological research and practice, an expansion encouraging constructive awareness and discussion in public forums. The centrality of mental health to overall wellbeing and the substantial contribution of external stressors has never been more apparent. The major influence of internal, biological stressors originating from alterations in energy metabolism has also earned significant consideration. In keeping with its extensive impact on physiology and health, growing evidence is accentuating the threat of obesity to central nervous system function and risk of psychiatric illness. Depression and anxiety disorders are prevalent and disabling mental health conditions and the increased hazard they pose for obese individuals is far-reaching. Beyond hindering personal welfare and quality of life, depressed mood and anxiety can diminish the will to seek out and adhere to therapeutic interventions. The interchange between metabolic and mood dysfunction can perpetuate a cycle of despair, overeating and physical inactivity that enhances obesity severity and numerous associated health risks. In view of these consequences and the limitations of available therapies, it is critical to improve our knowledge of the dietary, metabolic, and neurobiological effectors of depression and anxiety development and progression to implement better preventative and treatment strategies. An elevated body mass index (BMI) is predictive of a chronic course of depressive and anxiety symptoms [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar,2.Milaneschi Y. et al.Depression and obesity: evidence of shared biological mechanisms.Mol. Psychiatry. 2019; 24: 18-33Crossref PubMed Scopus (157) Google Scholar]. The odds of developing major depressive disorder (MDD) and anxiety increase as a function of the number of coexisting metabolic impairments, such as those characteristic of metabolic syndrome [3.Jokela M. et al.Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies.Mol. 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Psychiatry. 2021; 26: 4839-4852Crossref Scopus (15) Google Scholar]. Several lines of evidence suggest that prolonged inflammation caused by poor dietary lifestyle and inactivity and resulting metabolic consequences are required for such outcomes. Clinical observations combined with rodent models of obesity exhibiting depressive- and anxiety-like behaviors are proving valuable for uncovering the immunometabolic and neural mechanisms involved. In this review, we focus on how obesity increases the risk for depression and anxiety (for cognitive corollaries, see [7.Farruggia M.C. Small D.M. Effects of adiposity and metabolic dysfunction on cognition: a review.Physiol. Behav. 2019; 208: 112578Crossref PubMed Scopus (25) Google Scholar,8.Kendig M.D. et al.Unravelling the impacts of western-style diets on brain, gut microbiota and cognition.Neurosci. Biobehav. Rev. 2021; 128: 233-243Crossref PubMed Scopus (0) Google Scholar]), with the aim to illuminate the diverse metabolic culprits of obesity and their influence on the neural and behavioral processes giving rise to mood and emotional deficits. MDD (or depression) is a debilitating condition with genetic, epigenetic, and environmental contributions. Depression can manifest in various ways, modulating homeostatic functions such as appetite and sleep that can in turn further alter mood. Anxiety accompanies depression in most cases and is indicative of a poorer mental health prognosis. Melancholic depression, the most common form, is distinguished by hypophagia, hyposomnia, and anhedonia (decreased capacity to experience and anticipate pleasure). In addition to anhedonia, characteristics of the atypical subtype of depression include hyperphagia, lethargy, and hypersomnia. Obese individuals, particularly those presenting attributes of metabolic syndrome (abdominal obesity, hyperglycemia, hypertension, elevated triglycerides), tend to develop the atypical subtype [9.Milaneschi Y. et al.Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations.JAMA Psychiatry. 2017; 74: 1214-1225Crossref PubMed Scopus (90) Google Scholar] (Box 1). This form of depression has stronger links to peripheral [10.Rudolf S. et al.Elevated IL-6 levels in patients with atypical depression but not in patients with typical depression.Psychiatry Res. 2014; 217: 34-38Crossref PubMed Scopus (31) Google Scholar,11.Yoon H.K. et al.Role of cytokines in atypical depression.Nord. J. 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As atypical depression is predictive of overeating and weight gain, and metabolic risks can be intensified by antidepressant treatments that encourage weight gain, a vicious cycle can promote disease progression.Box 1Sex, gender, and metabolic risksThe frequency of depression and anxiety disorder diagnoses are approximately double for obese women as compared with obese men [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar,157.Scott K.M. et al.Age patterns in the prevalence of DSM-IV depressive/anxiety disorders with and without physical co-morbidity.Psychol. Med. 2008; 38: 1659-1669Crossref PubMed Scopus (0) Google Scholar], a divergence that corresponds with lifetime prevalence independent of body weight. This sex distinction in incidence narrows considerably in conditions of severe obesity (BMI ≥ 40) [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar]. While sex differences in anxiety disorders and major depression are well characterized, its only more recently that dissimilar underlying mechanisms are emerging (for review, see [158.Bangasser D.A. Cuarenta A. Sex differences in anxiety and depression: circuits and mechanisms.Nat. Rev. Neurosci. 2021; 22: 674-684Crossref PubMed Scopus (0) Google Scholar]). Adiposity serves as a better predictor of depression than body weight in women than in men [149.Ul-Haq Z. et al.Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants.BMC Psychiatry. 2014; 14: 153Crossref PubMed Scopus (16) Google Scholar]. Women with depression and anxiety are more likely to have increased appetite and weight gain than male counterparts [150.Kokras N. Dalla C. Preclinical sex differences in depression and antidepressant response: implications for clinical research.J. Neurosci. Res. 2017; 95: 731-736Crossref PubMed Scopus (16) Google Scholar], an outcome associated with the effects of stress to stimulate palatable food intake [119.Dallman M.F. Stress-induced obesity and the emotional nervous system.Trends Endocrinol. Metab. 2010; 21: 159-165Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar]. In both sexes, negative mood state is more robustly associated with metabolic impairments such as inflammation, hypertension, and insulin resistance rather than body weight itself [3.Jokela M. et al.Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies.Mol. Psychiatry. 2014; 19: 910-914Crossref PubMed Scopus (60) Google Scholar]. Correspondingly, the prevalence of MDD is nearly twice as high in people with type 2 diabetes [159.Wang F. et al.Prevalence of comorbid major depressive disorder in type 2 diabetes: a meta-analysis of comparative and epidemiological studies.Diabet. Med. 2019; 36: 961-969Crossref PubMed Scopus (19) Google Scholar] and more than threefold higher in people with type 1 diabetes than those without, with greater rates in diabetic women than men [160.Roy T. Lloyd C.E. Epidemiology of depression and diabetes: a systematic review.J. Affect. Disord. 2012; 142: S8-S21Crossref PubMed Scopus (538) Google Scholar]. Diabetes is associated with a 48% greater likelihood of anxiety symptoms and a 20% higher risk of developing an anxiety disorder [20.Gariepy G. et al.The longitudinal association from obesity to depression: results from the 12-year National Population Health Survey.Obesity (Silver Spring). 2010; 18: 1033-1038Crossref PubMed Scopus (48) Google Scholar]. In a consistent manner, obese individuals characterized as metabolically healthy (normal blood pressure, C-reactive protein, triglycerides, and glycaemia) present either no increased risk [161.Hamer M. et al.Risk of future depression in people who are obese but metabolically healthy: the English longitudinal study of ageing.Mol. Psychiatry. 2012; 17: 940-945Crossref PubMed Scopus (81) Google Scholar] or a modest elevated risk [3.Jokela M. et al.Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies.Mol. Psychiatry. 2014; 19: 910-914Crossref PubMed Scopus (60) Google Scholar] of depression diagnosis as compared with nonobese controls. However, obesity stigmatization and poor self-image may still contribute to negative mood states for these individuals, a problem more evident in women. The frequency of depression and anxiety disorder diagnoses are approximately double for obese women as compared with obese men [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar,157.Scott K.M. et al.Age patterns in the prevalence of DSM-IV depressive/anxiety disorders with and without physical co-morbidity.Psychol. Med. 2008; 38: 1659-1669Crossref PubMed Scopus (0) Google Scholar], a divergence that corresponds with lifetime prevalence independent of body weight. This sex distinction in incidence narrows considerably in conditions of severe obesity (BMI ≥ 40) [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar]. While sex differences in anxiety disorders and major depression are well characterized, its only more recently that dissimilar underlying mechanisms are emerging (for review, see [158.Bangasser D.A. Cuarenta A. Sex differences in anxiety and depression: circuits and mechanisms.Nat. Rev. Neurosci. 2021; 22: 674-684Crossref PubMed Scopus (0) Google Scholar]). Adiposity serves as a better predictor of depression than body weight in women than in men [149.Ul-Haq Z. et al.Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants.BMC Psychiatry. 2014; 14: 153Crossref PubMed Scopus (16) Google Scholar]. Women with depression and anxiety are more likely to have increased appetite and weight gain than male counterparts [150.Kokras N. Dalla C. Preclinical sex differences in depression and antidepressant response: implications for clinical research.J. Neurosci. Res. 2017; 95: 731-736Crossref PubMed Scopus (16) Google Scholar], an outcome associated with the effects of stress to stimulate palatable food intake [119.Dallman M.F. Stress-induced obesity and the emotional nervous system.Trends Endocrinol. Metab. 2010; 21: 159-165Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar]. In both sexes, negative mood state is more robustly associated with metabolic impairments such as inflammation, hypertension, and insulin resistance rather than body weight itself [3.Jokela M. et al.Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies.Mol. Psychiatry. 2014; 19: 910-914Crossref PubMed Scopus (60) Google Scholar]. Correspondingly, the prevalence of MDD is nearly twice as high in people with type 2 diabetes [159.Wang F. et al.Prevalence of comorbid major depressive disorder in type 2 diabetes: a meta-analysis of comparative and epidemiological studies.Diabet. Med. 2019; 36: 961-969Crossref PubMed Scopus (19) Google Scholar] and more than threefold higher in people with type 1 diabetes than those without, with greater rates in diabetic women than men [160.Roy T. Lloyd C.E. Epidemiology of depression and diabetes: a systematic review.J. Affect. Disord. 2012; 142: S8-S21Crossref PubMed Scopus (538) Google Scholar]. Diabetes is associated with a 48% greater likelihood of anxiety symptoms and a 20% higher risk of developing an anxiety disorder [20.Gariepy G. et al.The longitudinal association from obesity to depression: results from the 12-year National Population Health Survey.Obesity (Silver Spring). 2010; 18: 1033-1038Crossref PubMed Scopus (48) Google Scholar]. In a consistent manner, obese individuals characterized as metabolically healthy (normal blood pressure, C-reactive protein, triglycerides, and glycaemia) present either no increased risk [161.Hamer M. et al.Risk of future depression in people who are obese but metabolically healthy: the English longitudinal study of ageing.Mol. Psychiatry. 2012; 17: 940-945Crossref PubMed Scopus (81) Google Scholar] or a modest elevated risk [3.Jokela M. et al.Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies.Mol. Psychiatry. 2014; 19: 910-914Crossref PubMed Scopus (60) Google Scholar] of depression diagnosis as compared with nonobese controls. However, obesity stigmatization and poor self-image may still contribute to negative mood states for these individuals, a problem more evident in women. The link between obesity and depression is well established. There is a bidirectional association between being overweight (BMI ≥ 25–29.99) and depression in men and women, a relationship that is stronger for obesity (BMI ≥ 30) [15.Luppino F.S. et al.Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.Arch. Gen. Psychiatry. 2010; 67: 220-229Crossref PubMed Scopus (2217) Google Scholar]. A meta-analytic overview illustrates that obese adults self-reporting symptoms have 23–36% increased odds of developing depressed mood as compared with nonobese controls, whereas clinically diagnosed MDD is elevated by 14–34% [2.Milaneschi Y. et al.Depression and obesity: evidence of shared biological mechanisms.Mol. Psychiatry. 2019; 24: 18-33Crossref PubMed Scopus (157) Google Scholar]. The odds of depression are higher when evaluating the waist-to-hip ratio [16.Zhao G. et al.Waist circumference, abdominal obesity, and depression among overweight and obese U.S. adults: National Health and Nutrition Examination Survey 2005-2006.BMC Psychiatry. 2011; 11: 130Crossref PubMed Scopus (0) Google Scholar,17.Xu Q. et al.The relationship between abdominal obesity and depression in the general population: a systematic review and meta-analysis.Obes. Res. Clin. Pract. 2011; 5: e267-e360Crossref PubMed Scopus (0) Google Scholar] which provides a better estimate of visceral adiposity and metabolic dysfunction than BMI [18.Ross R. et al.Waist circumference as a vital sign in clinical practice: a consensus statement from the IAS and ICCR Working Group on Visceral Obesity.Nat. Rev. Endocrinol. 2020; 16: 177-189Crossref PubMed Scopus (167) Google Scholar]. Emphasizing the importance of early detection and treatment, a longitudinal meta-analysis suggests that obese adolescents have a 40% increased risk of being depressed [19.Mannan M. et al.Prospective associations between depression and obesity for adolescent males and females- a systematic review and meta-analysis of longitudinal studies.PLoS One. 2016; 11e0157240Crossref PubMed Scopus (37) Google Scholar]. A similar positive relationship is observed with anxiety: obesity heightens the odds of an anxiety disorder or anxiety symptoms (e.g., dread, unease) by 30% and 40%, respectively [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar,20.Gariepy G. et al.The longitudinal association from obesity to depression: results from the 12-year National Population Health Survey.Obesity (Silver Spring). 2010; 18: 1033-1038Crossref PubMed Scopus (48) Google Scholar]. As with depression, other variables may moderate the association between obesity and anxiety, including the degree of obesity, presence of cardiometabolic comorbidities, and the type of anxiety. Indeed, there is a stronger relationship between severe obesity (BMI ≥ 35) and anxiety [1.Zhao G. et al.Depression and anxiety among US adults: associations with body mass index.Int. J. Obes. 2009; 33: 257-266Crossref PubMed Scopus (161) Google Scholar]. Contemporary dietary environments offer an abundance of processed foods that are very tasty and abnormally energy-dense, in addition to foods that convey gustatory information associated with learned caloric value but then fall short post-ingestion (e.g., noncaloric sweeteners). Sensory cues remind us of their affective value and bombard us with information about their proximity and the comparatively low effort and cost required to obtain. These relatively recent changes to our external world perilously intersect with the neurobiological processes controlling feeding, which include critical components that favor positive emotion and stress reduction and facilitate the encoding of memories related to how to access these foods and how they make us feel in different contexts. Residing in midbrain and corticolimbic neural circuits, these processes are highly recruited by our modern food environment and are posited to be largely responsible for high rates of obesity and associated disease. Several lines of evidence link poor diet, inflammation, and depressive symptomology [21.Wang J. et al.Dietary inflammatory index and depression: a meta-analysis.Public Health Nutr. 2018; 22: 1-7Google Scholar,22.Chen G.Q. et al.Association between dietary inflammatory index and mental health: a systematic review and dose-response meta-analysis.Front. Nutr. 2021; 8: 662357Crossref PubMed Scopus (0) Google Scholar]. 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