Faculty Bibliography

Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager^-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD. [¹⁸F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUV_mean), ratio of SUV_iBAT/SUV_muscle (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [¹⁸F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVR_RKO-LFD: 2.14 +/- 0.10 and SUVR_RKO-LFD: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager ^-/-).

Background: Randomized-trial data on the long-term effects on infants' physical growth and neurodevelopment of the use of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) mothers are lacking. Methods: All 180 infants who completed the IN-US174-0174 study were offered participation in a long-term follow-up (LTFU) study.1 They were from CHB mothers who were randomly assigned (1:1 ratio) to receive usual care without antiviral therapy or to receive TDF from 30 to 32 weeks of gestation until postpartum week 4. For the LTFU study, infants were assessed at the ages of 72, 120 and 192 weeks for growth and neurodevelopment with Bayley-III measurement. Their bone mineral density (BMD) was measured at week 192. The neurodevelopmental delay was defined by cognitive and language composite scores <85 (1 SD below the mean of 100).2 These parameters were compared between the TDF-exposed and TDFunexposed groups. Results: Among 180 infants completed in the initial study, 176 (98%) participated in the LTFU study and 144 (82%) completed the LTFU. In the TDF-exposed group, the mean (+/-SD) duration of fetal exposure to TDF was 8.57+/-0.53 weeks. The gestational age, delivery mode, weight, height, and Apgar score at birth were similar in the two groups. At week 192, there was no significant difference in the pre-specified outcomes between groups including head circumference, height, BMD, cognitive, social-emotional, and adaptive behavior measurements between groups. There was no neurodevelopmental delay in the cohort. In the TDF-exposed group, children had significantly higher motorcomposite scores (146.46+/-6.39 vs 142.88+/-9.54; p=0.009) and boys had significantly lower mean body weight (18.48+/-2.35kg vs 19.84+/-3.46kg; p= 0.029). However, the boys' mean body weight in the TDF-exposed group was significantly higher than that of the national Chinese reference value of 4-year-old boys (18.48+/-2.35kg vs 16.64+/-1.89; p=0.010).3Conclusion: Among infants with fetal exposure to TDF, the physical growth, BMD, and neurodevelopment were similar to those without the exposure and within the normal range of Chinese reference values during 192-week follow-up. Our data support the safety of using TDF during the third trimester in mothers with CHB. Acknowledgment: (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.) References: Pan CQ, Duan Z, Dai E, et al. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. N Engl J Med 2016;374:2324-34. Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr Res 2014;75:670-4. Li H. [Growth standardized values and curves based on weight, length/ height and head circumference for Chinese children under 7 years of age]. Zhonghua Er Ke Za Zhi 2009;47:173-8. (Table Presented)

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[¹¹C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH_MAX r = 0.87, p = .001; cortisol_MAX r = 0.86, p = .002; amygdala: ACTH_MAX r = 0.86, p = .002; cortisol_MAX r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol_MAX, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.

PURPOSE/OBJECTIVE:Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. METHODS:C]O-methylreboxetine (MRB) before and 6 months after dietary intervention. RESULTS: = 0.80; p < 0.0001). No changes were observed in non-obese controls. CONCLUSION/CONCLUSIONS:These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

Context/UNASSIGNED:Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated diabetic patients, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses. Objective/UNASSIGNED:To examine the potential role of brain noradrenergic activation in humans during hypoglycemia. Design/UNASSIGNED:A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with PET imaging. Participants/UNASSIGNED:Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp. Design/UNASSIGNED:Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine, [11C]MRB, a highly selective norepinephrine transporter (NET) ligand, at baseline and during hypoglycemia. Results/UNASSIGNED:Hypoglycemia increased plasma epinephrine, glucagon, cortisol and growth hormone, and decreased [11C]MRB binding potential (BPND) by 24 ± 12% in the raphe nucleus (P<0.01). In contrast, changes in [11C]MRB (BPND) in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P<0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane. Conclusions/UNASSIGNED:Insulin-induced hypoglycemia initiated a complex brain noradrenergic response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity and hunger, was observed to have increased noradrenergic activity, while the hypothalamus showed a NET-binding pattern that was associated with the individual's CR response magnitude. These findings suggest that noradrenergic output most likely is important for modulating brain responses to hypoglycemia in humans.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD), but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter (NET) which might account for its therapeutic efficacy. Method: In this study, we used positron emission tomography (PET) with 11C-MRB to estimate NET density and assess the relationship between NET occupancy by quetiapine XR and improvement in depression in patients with MDD (n=5) and BD (n=5). After the baseline PET scan, patients were treated with quetiapine XR with a target dose of 150 mg in MDD and 300 mg in BD. Patients had a second PET scan at the end of week 2, and a final scan at week 7. Results: NET density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and NET occupancy in locus ceruleus at week 2. The NET occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% NET occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% NET occupancy was 36.8 microg/L. Conclusion: These data provide preliminary support for the hypothesis that NET occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8+/-9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.