Prenatal stress-immune programming of sex differences in comorbidity of depression and obesity/metabolic syndrome.
Major depressive disorder (MDD) is the number one cause of disability worldwide and is comorbid with many chronic diseases, including obesity/metabolic syndrome (MetS). Women have twice as much risk for MDD and comorbidity with obesity/MetS as men, although pathways for understanding this association remain unclear. On the basis of clinical and preclinical studies, we argue that prenatal maternal stress (ie, excess glucocorticoid expression and associated immune responses) that occurs during the sexual differentiation of the fetal brain has sex-dependent effects on brain development within highly sexually dimorphic regions that regulate mood, stress, metabolic function, the autonomic nervous system, and the vasculature. Furthermore, these effects have lifelong consequences for shared sex-dependent risk of MDD and obesity/MetS. Thus, we propose that there are shared biologic substrates at the anatomical, molecular, and/or genetic levels that produce the comorbid risk for MDD-MetS through sex-dependent fetal origins.
Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Departments of Psychiatry and Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Jill M
JM
Goldstein
Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Departments of Psychiatry and Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Laura
L
Holsen
Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Grace
G
Huang
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
Bradley D
BD
Hammond
Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
Tamarra
T
James-Todd
Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Departments of Psychiatry and Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Sara
S
Cherkerzian
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
Taben M
TM
Hale
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
Robert J
RJ
Handa
D015897:Comorbidity; D003865:Major Depressive Disorder / Q000453:epidemiology / Q000503:physiopathology*; D005260:Female; D006066:Gonads / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000503:physiopathology*; D009765:Obesity / Q000453:epidemiology / Q000503:physiopathology*; D010913:Pituitary-Adrenal System / Q000502:physiology / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology / Q000503:physiopathology*; D012727:Sex Characteristics; D013312:Stress, Physiological / Q000276:immunology / Q000502:physiology; D013315:Stress, Psychological / Q000276:immunology / Q000503:physiopathology
depression; depression-cardiometabolic comorbidity; fetal programming; inflammation; obesity/metabolic syndrome; prenatal stress model; sex difference