Metabolic Reprogramming by 3-Iodothyronamine (T1AM): A New Perspective to Reverse Obesity through Co-Regulation of Sirtuin 4 and 6 Expression.

Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes.

The influence of depression on the relationship between loneliness and grief trajectories in bereaved older adults.

Loneliness is associated with adverse mental health outcomes in older adults. Bereavement triggers intense feelings of loneliness. This pilot study explored the association between baseline loneliness and grief symptom trajectories in bereaved elders and explored if this association is moderated by depressive symptom changes. 56 individuals aged 50 years and older, within 13-months following bereavement, completed assessments. Loneliness was measured at baseline using the UCLA loneliness scale-version 3. Grief and depressive symptoms were measured over 26 weeks using the inventory of complicated grief (ICG) and the 17-item Hamilton Depressive Rating (HAM-D) scales, respectively. Linear regression explored the cross-sectional association between loneliness and grief symptoms, after adjusting for covariates including depressive symptoms. A mixed-effects linear model tested whether baseline loneliness was related to grief symptom trajectory over 26 weeks, after accounting for depressive symptom changes. Loneliness was associated with grief symptom severity at baseline; however, this cross-sectional association was not significant after adjusting for depressive symptoms. Longitudinally, baseline loneliness was positively associated with grief symptom trajectories; however, depressive symptom changes moderated this association. Depressive symptom alterations appear to weaken the loneliness-grief symptom change association. These exploratory findings point to opportunities for interventions targeting loneliness and depression that may reduce grief intensity over time in bereaved elders.

Commitment, confidence, and concerns: Assessing health care professionals' child maltreatment reporting attitudes.

Given that childhood maltreatment is a significant international public health problem contributing to all major morbidity and mortality determinants, there is need to explore current practices and readiness of health care professionals (HCPs) to assess maltreatment, identify maltreatment risk factors, and complete mandated reporting. HCPs (N=114) completed a child maltreatment mandated reporting measure to assess level of comfort with mandated reporting, commitment to the reporting role, and confidence in the child protection system to take action as needed. Additional questions explored comfort discussing maltreatment and risk factors for maltreatment in a medical setting and knowledge of community resources. Results indicated that HCPs were committed to their mandated reporting role and did not perceive substantial potential negative consequences of reporting. However, there were concerns regarding lack of confidence in the system's ability to respond sufficiently to reports. Despite commitment to the reporting role, results showed that large proportions of HCPs do not routinely screen for maltreatment, feel uncomfortable discussing maltreatment history, and lack knowledge about community resources. Additional training efforts must be prioritized in health care systems to improve short- and long-term health outcomes.

Optical imaging of mitochondrial redox state in rodent models with 3-iodothyronamine.

This study used an optical technique to measure the effects of treating low (10 mg/kg) and high (25 mg/kg) doses of 3-iodothyronamine (T1AM) on the metabolism in the kidney and heart of mice. The ratio of two intrinsic fluorophores in tissue, (NADH/FAD), called the NADH redox ratio (NADH RR), is a marker of the metabolic state of the tissue. A cryofluorescence imaging instrument was used to provide a quantitative assessment of NADH RR in both kidneys and hearts in mice treated with 3-iodothyronamine. We compared those results to corresponding tissues in control mice. In the kidneys of mice treated with a high dose T1AM, the mean values of the maximum projection of NADH RR were 2.6 ± 0.6 compared to 3.20 ± 0.03 in control mice, indicating a 19% (± 0.4) significant increase in oxidative stress (OS) in the high dose-treated kidneys (P = 0.047). However, kidneys treated with a low dose of T1AM showed no difference in NADH RR compared to the kidneys of control mice. Furthermore, low versus high dose treatment of T1AM showed different responses in the heart than in the kidneys. The mean value of the maximum projection of NADH RR in the heart changed from 3.0 ± 0.3 to 3.2 ± 0.6 for the low dose and the high dose T1AM-treated mice, respectively, as compared to 2.8 ± 0.7 in control mice. These values correspond to a 9% (±0.5) (P = 0.045) and 14% (±0.5) (P = 0.008) significant increase in NADH RR in the T1AM-treated hearts, indicating that the high dose T1AM-treated tissues have reduced OS compared to the low dose-treated tissues or the control tissues. These results suggest that while T1AM at a high dose increases oxidative response in kidneys, it has a protective effect in the heart and may exert its effect through alternative pathways at different doses and at tissue specific levels.