Amygdalar Metabolic Activity Independently Associates With Progression of Visceral Adiposity

Amorina Ishai; Michael T. Osborne; Brian Tung; Ying Wang; Basma Hammad; Tomas Patrich; Blake Oberfeld; Zahi A. Fayad; Jon T. Giles; Janet Lo; Lisa M. Shin; Steven K. Grinspoon; Karestan C. Koenen; Roger K. Pitman; Ahmed Tawakol


J Clin Endocrinol Metab. 2019;104(4):1029-1038. 

In This Article

Abstract and Introduction


Context: Epidemiologic data link psychological stress to adiposity. The underlying mechanisms remain uncertain.

Objectives: To test whether (i) higher activity of the amygdala, a neural center involved in the response to stress, associates with greater visceral adipose tissue (VAT) volumes and (ii) this association is mediated by increased bone marrow activity.

Setting: Massachusetts General Hospital, Boston, Massachusetts.

Patients: Two hundred forty-six patients without active oncologic, cardiovascular, or inflammatory disease who underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging were studied. VAT imaging was repeated ~1 year later in 68 subjects.

Design: Metabolic activity of the amygdala (AmygA), hematopoietic tissue activity, and adiposity volumes were measured with validated methods.

Main Outcome Measure: The relationship between AmygA and baseline and follow-up VAT.

Results: AmygA associated with baseline body mass index (standardized β = 0.15; P = 0.01), VAT (0.19; P = 0.002), and VAT/subcutaneous adipose tissue ratio (0.20; P= 0.002), all remaining significant after adjustment for age and sex. AmygA also associated with bone marrow activity (0.15; P = 0.01), which in turn associated with VAT (0.34; P < 0.001). Furthermore, path analysis showed that 48% of the relationship between AmygA and baseline VAT was mediated by increased bone marrow activity (P = 0.007). Moreover, AmygA associated with achieved VAT after 1 year (P = 0.02) after adjusting for age, sex, and baseline VAT.

Conclusions: These results suggest a neurobiological pathway involving the amygdala and bone marrow linking psychosocial stress to adiposity in humans. Future studies should test whether targeting this mechanism attenuates adiposity and its complications.


Obesity is a rapidly growing threat to health across the world,[1,2] which independently increases the risk for cardiovascular disease (CVD), malignancy, and all-cause mortality.[3,4] Body fat distribution, specifically increased visceral adipose tissue (VAT), is a better predictor of disease than body mass index (BMI) or total body fat mass.[5–8] A large body of evidence demonstrates that in addition to adverse health behaviors (e.g., poor diet and physical inactivity), chronic psychosocial stress is an important independent risk factor for adiposity.[9,10] Nevertheless, the assessment and management of stress are not core components of most current weight loss approaches, partly because of inadequate understanding of the mechanisms connecting stress to adiposity. Clarification of these mechanisms may facilitate lifestyle and pharmacologic interventions to limit the expansion of adiposity and its complications.

It is a common misconception that stress leads to increased adiposity solely through an increase in adverse health behaviors, particularly increased intake of less healthy foods. In fact, animals chronically exposed to stressful stimuli have increased visceral fat depots despite comparable or lower food intake.[11,12] Similarly, in some but not all human studies, stress associates with adiposity and metabolic impairment independently of diet and physical activity, and it lowers the threshold at which adverse adiposity develops for a given diet.[13–15] Release of monocytes from hematopoietic tissues appears to play an important role in this connection. In animal models, stress triggers increased hematopoietic stem and progenitor cell proliferation within the bone marrow and accelerates immune cellular output.[16–20] These stress-induced monocytes subsequently infiltrate VAT, prompt adipocyte dysfunction, and promote VAT expansion.[21,22] However, it is unknown whether a homologous association among stress, hematopoietic activity, and VAT exists in humans. Moreover, the role of the brain in this mechanism remains undetermined.

Studies evaluating the effect of stress on human physiology have been facilitated by advanced neuroimaging methods, which provide objective measures of the neurobiological response to stress.[23–26] The amygdala is part of an endogenous circuitry within the brain that mediates neuroendocrine, autonomic, and behavioral changes in response to stress.[27,28] Resting metabolic activity in the amygdala (AmygA) can be reproducibly quantified using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging. AmygA is relatively stable over time[29,30] and associates with an individual's perceived stress.[25] The amygdala is conditioned by chronic stress, and increased amygdalar metabolic activity and activation have been noted in chronic stress-related disorders such as posttraumatic stress disorder and anxiety.[23,31–33] Furthermore, AmygA is linked to adverse pathologic consequences of chronic stress.[25,26] Our group recently observed that higher AmygA leads to future CVD events in humans through a serial mechanism that involves increased hematopoietic tissue activity, with the putative release of inflammatory white blood cells, and increased arterial inflammation and predicts the development of incident diabetes mellitus independently of adiposity.[25,26] Moreover, using positron emission tomography (PET)/CT, AmygA and bone marrow activity can be quantified by 18F-FDG uptake, along with simultaneous measurement of adipose tissue volumes with CT, thereby making this modality uniquely suitable for investigating the possible biological connections among these systems. Accordingly, we analyzed the data from brain and body 18F-FDG PET/CT imaging to evaluate the hypotheses that (i) higher AmygA associates with greater baseline VAT volume and with greater achieved VAT volume after 1 year and (ii) increased bone marrow activity mediates the relationship between AmygA and VAT.