Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity

Abstract

Background: The notion that exposure to chronic stress predisposes individuals to developing type 2 diabetes (T2D) has gained much attention in recent decades. Long-term stress induces neuroadaptation in the amygdala and increases corticosterone levels. Corticosterone, the major stress hormone in rodents, induces insulin resistance and obesity in mice. However, little is known about whether the stress-induced amygdalar neuroadaptation could promote the risk of T2D. Methods: We used an 11-week high-fat diet (HFD) feeding paradigm to induce insulin dysfunction in mice, followed by implementation of a 10-day social defeat (SD) stress protocol. Results: Mice receiving SD at the beginning of the HFD feeding aggravated HFD-induced insulin resistance and white adipose tissue expansion. HFD mice had higher levels of plasma corticosterone, which was not affected by the SD. The SD stress upregulated the expression of TrkB and synaptotagmin-4 in the amygdala of HFD mice. Bilateral lesions of the central amygdalae before SD stress inhibited the stress-induced aggravating effect without affecting the HFD-induced elevation of plasma corticosterone. Conclusions: Stress aggravates HFD-induced insulin resistance and neuroadaptation in the amygdala. The HFD-induced insulin resistance is amygdala-dependent. Understanding the role of stress-induced amygdalar adaptation in the development of T2D could inform therapies aimed at reducing chronic stressors to decrease the risk for T2D.

Disrupted hypothalamic CRH neuron responsiveness contributes to diet‐induced obesity

“…Chronic stress induces a sustained increase in the activity of PVH CRH neurons [41], which may mimic the effect induced by NachBac in clamping the neuron activity at high levels. Thus, disrupted neuron responsiveness may explain obesity development induced by chronic stressors (e.g., social stress) [42,43] and synergistic effects between chronic stress and HFD on obesity development [6][7][8][9]. Given the socioeconomic stress faced by humans is chronic in nature, and a positive correlation between cort levels and low socioeconomic status [44], our results support that chronic stress contributes significantly to obesity development, especially in the current HFD environment.…”

“…Specifically, HFD feeding is associated with disrupted diurnal rhythms in feeding and metabolism, and time-scheduled feeding alleviates the obesity and associated metabolic syndromes by HFD [5], suggesting an important contribution of disrupted diurnal rhythms to diet-induced obesity (DIO). Recent studies have also suggested a potential role for stress in worsening DIO [6][7][8][9]. Despite intense research, the cellular mechanism in the brain underlying HFD feeding and its potential interaction with stress in obesity development remains elusive.…”

Inhibitory Effects of Trifluoperazine on Peripheral Proinflammatory Cytokine Expression and Hypothalamic Microglia Activation in Obese Mice Induced by Chronic Feeding With High-Fat-Diet

“…Animals that received saline served as the control group (vehicle). Blood samples were collected at 3 h from the retro-orbital sinuses of anesthetized mice using a heparinized capillary tube (Tsai et al, 2018 ). Alternatively, under anesthesia, blood samples were collected at 6 h via cardiac puncture using a 26G needle rinsed with 10 μl of heparin (5,000 IU/ml; Leo Pharmaceutical, Ltd., Denmark).…”

The Dopamine D2R Antagonist Trifluoperazine Suppresses High-Fat Diet-Induced Hyperglycemia and Hypothalamic Gliosis in Obese Mice

“…Animals that received saline served as the control group (vehicle). Blood samples were collected at 3 h from the retro-orbital sinuses of anesthetized mice using a heparinized capillary tube 29 . Alternatively, under anesthesia, blood samples were collected at 6 h via cardiac puncture using a 26G needle rinsed with 10 ml of heparin (5000 IU/mL; Leo Pharmaceutical, Ltd., Denmark).…”