We then found significant interaction effect of between diet (chow vs. HFD) and SD_SI (control vs. SD vs. SD+SI) on glucose levels measured at week 16 (F(2, 57)=4.11, p=0.021). Post-hoc analyses showed that if the subjects were feed with HFD or been SD+SI, the glucose level was significant higher then controls.
Besides, the main effect of diet on insulin level (F(1, 106)=29.53, p<0.001) and HOMA-IR (F(1, 53)=13.42, p=0.001) was significant, which showed that the HFD group has higher insulin level and HOMA-IR then chow group.
Additionally, although the interaction effect was not significant, both diet and social stress had a main
effect on oxytocin level, indicating significant changes of oxytocin levels in animals exposed to a HFD (F(1, 117)= 6.73, p=0.011), and SD (F(2, 117)= 28.12, p<0.001) when compared with controls. HFD group has a higher level of oxytocin then chow group. Post-hoc analyses showed that SD+SS group had highest oxytocin level, control group had central oxytocin level, and the SD+SI group had lowest oxytocin level.
Figure 5. The glucose tolerance test (IPGTT) and fasting glucose levels. (a) Plasma glucose concentration curve during IPGTT and (b) fasting glucose level for chow and HFD groups. Data were analyzed with 2 way ANOVA. Values are mean ± standard error of the mean,*p < 0.05. chow, n=4; HFD, n=3; SD-chow, n=7; SD-HFD, n=7.
Figure 6. The glucose level and HOMA-IR index in chow or high fat diet (HFD) fed B6 mice in either socially isolated or non-isolated conditions. Eight-week-old C57BL/6 male mice fed with 8 weeks normal chow or HFD after social defeat. (a) the glucose levels of all groups. C how group: ctrl, n=13, SD+SI, n=7, SD+SS, n=12. HFD group: ctrl, n=14; SD+SI, n=8; SD+SS, n=9. (b) the HOMA-IR index of all groups. C how group: ctrl, n=13, SD+SI, n=6, SD+SS, n=9. HFD group: ctrl, n=12; SD+SI, n=8; SD+SS, n=9. Values are mean ± standard error of the mean,*p < 0.05, **p < 0.01.
Figure 7. The effects of social defeat on peripheral oxytocin levels in chow or high fat diet (HFD) fed B6 mice in either socially isolated or non-isolated conditions. Eight-week-old C57BL/6 male mice fed with 8 weeks normal chow or HFD after social defeat. (a) the oxytocin levels of chow group. (ctrl, n=21, SD+SI, n=13, SD+SS, n=16). (b) the oxytocin levels of HFD group. (ctrl, n=21; SD+SI, n=12; SD+SS, n=13) (c) The oxytocin levels of all groups.*p < 0.05, **p < 0.01 vs group-ctrl; #p <0.05, ## <0.01, vs chow-ctrl; ▲▲
p < 0.01, vs group SD+SI, ★p<0.05, vs chow-SD+SI.
SD and HFD alter brain dopaminergic activity
At week 16, the interaction effects between diet and between SD (control vs. SD) on the dopamine D2 receptor specific binding ratio (SBR) at striatum and midbrain were significant (striatum: F(1, 11)=6.62, p=
0.026; midbrain: F(1, 11)=10.05, p= 0.009) and were marginally significant at hippocampus (F(1, 11)=4.68, p= 0.053) and at amygdala (F(1, 11)=3.77, p= 0.078). Post-hoc analyses showed a tendency that if the subjects were feed with HFD or been SD, the SBRs at striatum, hippocampus, and midbrain were lower than controls.
However, although the SD effect in amygdala was same as others regions, the diet effect was opposite.
Namely, if the subjects were feed with HFD, the SBR at amygdala was higher than controls.
Figure 8. Ex vivo autoradiography in brain from mice administered the I-123 Epidepride, a radio-ligand with high affinity for D2 receptors. The specific binding ratio in (a) striatum; (b) hippocampus, amygdala and midbrain. Chow control, n=3; SD-chow, n=4; HFD, n=4; SD-HFD, n=4.
E x V IV O
Figure 9. The effects of social stress and HFD feeding on dopamine transporter (DAT) expression levels.
(a) Representative western blots of DAT levels in striatum of control chow, HFD, SD-chow, and SD-HFD mice. (b) Quantification of DAT normalized by GAPDH levels in striatum. Control chow, n=2; HFD, n=2;
SD-chow, n=2; SD-HFD, n=2.
Fig 10. The positron emission tomography (PET) with 18F-labeled fluoro-2-deoxyglcose (18F-FDG) scan in striatum. (a) The cumulative curve of 18F-FDG uptake in striatum throughout a 3000-second scanning course. (b) The peak of 18F-FDG uptake at 180 second in striatum of control chow, SD-chow, and SD-HFD mice. Values are mean ± standard error of the mean,*p < 0.05 compared to control chow group. Control chow, n=3; SD-chow, n=3; SD-HFD, n=3.
Results from human studies:
The manuscript has been published in Clinical Psychopharmacology and Neuroscience 2019 Nov; 17(4):
487-494.
The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression Tsung-Yu Tsai 1, Huai-Hsuan Tseng 1, Mei Hung Chi 1, Hui Hua Chang 1, Cheng-Kuan Wu 1, Yen Kuang Yang 1, Po See Chen 1*
1Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 1Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Objective: Loneliness is a specific risk factor for depressive symptoms and suicidal behavior. The present study examined whether the serum oxytocin level would interact with social support and buffers loneliness and HPA-axis activity in drug-naïve patients with major depressive disorder (MDD).
Methods: Twenty-six (M:F=3:23, age: 45.54±12.97) patients with MDD were recruited. The 17-item Hamilton depression rating scale, UCLA Loneliness Scale and self-reported Measurement of Support Function questionnaire were administered. Serum oxytocin and cortisol levels were assessed using a commercial immunoassay kits.
Results: In MDD patients, a negative association was found between degrees of social support and loneliness (β =-0.39, p=0.04). The interaction between social support and serum oxytocin level was negatively associated with loneliness (β=−0.50, p=0.017) and serum cortisol level (β=−0.52, p=0.020) after adjusting for age. Follow-up analyses showed that the association between higher social support and lower loneliness was observed only in the higher-oxytocin group (r = −0.75, p = 0.003) but not in the lower group (r = −0.19, p = 0.53). The significance remained after further adjusting for sex and depression severity.
Conclusion: Low oxytocin level is a vulnerability factor for the buffering effect of social support for loneliness and aberrant hypothalamic-pituitary-adrenal (HPA)-axis activity in MDD patients.
Keywords: cortisol, loneliness, major depression, oxytocin, social support
The manuscript has been published in Diabetes Metabolic Syndrome and Obesity 2019 Dec 19;12:2707-2713.
The OXTR Polymorphism Stratified the Correlation of Oxytocin and Glucose Homeostasis in Non-diabetic Subjects
Hui Hua Chang1,2,3a, Wei Hung Chang4,a, Mei Hung Chi4, Yi Chin Peng1, Chih-Chun Huang4, Yen Kuang Yang4,5,6, Po See Chen4,5*
1Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3 Department of Pharmacy, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
4Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
6Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
a These authors contributed equally to the study
Objective: Previous animal studies have shown that the oxytocin system might affect glucose homeostasis through the hypothalamus–pituitary–adrenal (HPA) axis and peripheral organs. Moreover, whether the effect is stratified by the polymorphism of oxytocin receptor gene (OXTR) remains unclear.
Methods: In this study, we recruited 89 non-diabetic participants. Their plasma oxytocin and serum insulin profiles were obtained, and the polymorphism of OXTR rs53576 was genotyped.
Results: There were significant correlations between the oxytocin level and fasting glucose level (r = –0.29, P
<0.01), insulin level (r = –0.26, P = 0.01), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (r = –0.25, P = 0.01), when adjusted for age, gender, and body mass index (BMI). When further considering the stratification effects of OXTR variation, we found that the oxytocin level was significantly correlated with the fasting glucose level (r = –0.25, P = 0.04), insulin level (r = –0.35, P = 0.03), and HOMA-IR (r = –0.35, P < 0.01) in subjects with the OXTR A allele adjustment for age, gender, and BMI. In addition, the oxytocin level in those with the GG genotype of OXTR was significantly negatively correlated with the leptin level (r = –0.66, P = 0.02).
Conclusion: The results demonstrated that the polymorphism of OXTR plays an important role in individual differences in the correlation of oxytocin and glucose homeostasis in non-diabetic subjects.
Keywords: glucose, insulin, oxytocin, OXTR, polymorphism.
The manuscript has been published in Translational Psychiatry 2020 Aug;10:281~1-281~8.
Dysregulation of oxytocin and dopamine in the corticostriatal circuitry in bipolar II disorder
Shyh-Yuh Wei a, Huai-Hsuan Tseng a,b, Hui Hua Chang c,d,e,f, Tsung-Hua Lu a, Wei Hung Chang a,g, Nan Tsing Chiu h, Yen Kuang Yang a,b,i, Po See Chen a,b,g*
a Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
b Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
c Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
d School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
e Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
f Department of Pharmacy, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
g Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
h Department of Nuclear Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
i Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan
*Corresponding author: Po See Chen
Department of Psychiatry, National Cheng Kung University Hospital, 138 Sheng Li Road, North Dist., Tainan 70403, Taiwan.
Tel.: +886 6 2353535 x5189; fax: +886 6 2759259.
Email: [email protected]
The oxytocin (OXT) and dopamine systems synergistically facilitate striatal reactivity. Abnormal striatal activation has repeatedly been observed in patients with bipolar disorder (BD); however, such abnormality remains unclear in BD II. Here we aimed to investigate whether the corticostriatal connectivity was altered and the possible relationships among corticostriatal connectivity, OXT, and dopamine systems in BD II.
Twenty-five BD II patients, as defined by the DSM-V, and 29 healthy controls (HC) were enrolled in this study.
Plasma OXT was measured and striatal dopamine transporter (DAT) availability was assessed using [99mTc]TRODAT-1 single-photon emission computed tomography (SPECT). Brain network functional connectivity (FC) was measured during the resting-state using functional magnetic resonance imaging, and the dorsal caudate (DC) was selected as the seed region. The results showed that the OXT level was significantly lower in the BD II patients, while the striatal DAT availability was not significantly different between the BD II and HC groups. The BD II patients exhibited significantly lower FC between the DC and the executive control network (dorsolateral prefrontal, anterior cingulate cortex, and posterior parietal cortex) as compared with the HC. Only observed in HC, the DC-posterior parietal cortex FC was negatively correlated with the OXT level and striatal DAT availability. Our findings in the HC support a model in which the OXT and dopamine systems act in tandem to regulate corticostriatal circuitry, while the synergistic interaction was perturbed in BD II.
Taken together, these results implied a maladaptive neuroplasticity in BD II.