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"Loh, H."
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A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue
Mutations in the leptin gene (
ob
) result in a metabolic disorder that includes severe obesity
1
, and defects in thermogenesis
2
and lipolysis
3
, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that
ob/ob
mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of
ob/ob
mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNF
PVH
). Deletion of BDNF
PVH
blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.
The authors show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.
Journal Article
Ecology of zoonoses: natural and unnatural histories
More than 60% of human infectious diseases are caused by pathogens shared with wild or domestic animals. Zoonotic disease organisms include those that are endemic in human populations or enzootic in animal populations with frequent cross-species transmission to people. Some of these diseases have only emerged recently. Together, these organisms are responsible for a substantial burden of disease, with endemic and enzootic zoonoses causing about a billion cases of illness in people and millions of deaths every year. Emerging zoonoses are a growing threat to global health and have caused hundreds of billions of US dollars of economic damage in the past 20 years. We aimed to review how zoonotic diseases result from natural pathogen ecology, and how other circumstances, such as animal production, extraction of natural resources, and antimicrobial application change the dynamics of disease exposure to human beings. In view of present anthropogenic trends, a more effective approach to zoonotic disease prevention and control will require a broad view of medicine that emphasises evidence-based decision making and integrates ecological and evolutionary principles of animal, human, and environmental factors. This broad view is essential for the successful development of policies and practices that reduce probability of future zoonotic emergence, targeted surveillance and strategic prevention, and engagement of partners outside the medical community to help improve health outcomes and reduce disease threats.
Journal Article
Built environment and physical activity among adolescents: the moderating effects of neighborhood safety and social support
Background
Increasing emphasis has been placed on improving physical activity levels through multilevel interventions. This study aims to examine moderating effects of neighborhood safety (crime and traffic) and social support (from parent and sibling/peer) for physical activity in the relationship between the built environment and moderate-to-vigorous physical activity (MVPA) outside school hours among adolescents in Melbourne.
Methods
Data were from the NEighbourhood Activity in Youth study conducted among adolescents in Melbourne, Australia (
n
= 358, 15.3 (SD = 1.5) years). MVPA outside school hours was assessed by accelerometer. Built environment features within 1 km and 2 km residential buffers including recreation facilities, park area, and walkability and its components were assessed using Geographic Information Systems. Neighborhood safety, social support for physical activity and sociodemographic information were self-reported by adolescents. Multilevel linear regression models were used to estimate associations.
Results
Support for physical activity from sibling/peer positively moderated the relationship between recreation facilities (1 km), residential density (2 km) and MVPA. Recreation facility (count within 2 km), walkability (1 km and 2 km) and residential density (1 km) had significant positive associations with MVPA outside school hours.
Conclusion
The built environment appeared to have stronger facilitating effects on MVPA among adolescents who had favourable support for physical activity from their sibling or peer. Multilevel interventions that target the built environment and social factors are needed to promote MVPA outside school hours among adolescents.
Journal Article
The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep
Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington's disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.
Journal Article
Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson’s disease
Mutations in
PINK1
cause early-onset Parkinson’s disease (PD). Studies in
Drosophila melanogaster
have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in
Drosophila pink1
mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring
PINK1
mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of
pink1
mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.
Mutations in
PINK1
cause early-onset Parkinson’s disease. Martins and colleagues find that the expression levels of genes involved in nucleotide metabolism are upregulated in a
Drosophila pink1
mutant, and that this affects neuronal mitochondrial DNA synthesis. They find that enhancing nucleotide synthesis through genetics or pharmacological approaches rescues mitochondrial defects associated with
PINK1
mutations.
Journal Article
Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD
+
) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD
+
-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD
+
protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD
+
or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human
PARP1
gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD
+
by either vitamin B supplements or the inhibition of NAD
+
-dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease.
Journal Article
Long-Term Mortality Risk in Older Adults with Sarcopenia: An 11-Year Prospective Cohort Study Comparing AWGS 2014 and AWGS 2019 Guidelines for Enhanced Clinical Utility and Accurate Risk Prediction
To discern the diagnostic accuracy between the updated diagnostic consensus of the Asian Working Group for Sarcopenia (AWGS) in 2019 (AWGS 2019) and the previous AWGS 2014 guidelines.
A prospective population-based cohort study.
The study included 731 older community-dwelling adults aged ≥ 65 years who participated in face-to-face interviews and were followed up for 11-year mortality until 31 Mar 2022.
We utilized a handgrip strength dynamometer to measure participants' muscle strength, while their walking speed was determined by a timed 6-meter walk test at their usual pace. Additionally, muscle mass was measured using dual-energy X-ray absorptiometry scanning. Sarcopenia was defined as the presence of low muscle mass in combination with weakness and/or slowness both by AWGS 2014 and 2019 criteria.
The present study followed 731 participants (mean age 73.4 ± 5.4 years, men predominant 52.8%) over a period of 11 years, yielding 5927 person-years and 159 deaths. Prevalence of sarcopenia defined by AWGS 2019 and 2014 criteria were 8.5% and 6.8%, respectively. Sarcopenia defined by AWGS 2019 (HR 1.62, 95% CI 1.04–2.54, p=0.034) but not AWGS 2014 was significantly associated with mortality in community-living older adults after adjusting for potential confounders such as age, sex, education, drinking, disease burden and serum level of testosterone. The study also found that the AWGS 2019 criteria had a better model fitness than AWGS 2014 criteria in predicting mortality.
AWGS 2019 criteria outperformed AWGS 2014 in identifying sarcopenia risk and predicting mortality. Screening for sarcopenia in older adults may improve health outcomes by identifying those at increased mortality risk.
Journal Article
Outdoor public recreation spaces and social connectedness among adolescents
Background
Outdoor public recreation spaces are important settings for leisure and physical activity. Adolescents’ use of these spaces may contribute to social connectedness via social interaction with peers and the community in these settings. However, research on this topic is limited. This exploratory study examined associations of frequency of visitation and physical activity in outdoor public recreation spaces with social connectedness among adolescents in Melbourne, Australia.
Methods
Adolescents self-reported their frequency of visitation to parks, trails, beach/lake, and sports facilities; frequency of physical activity in a park, local street or path, and their street; and social connectedness. Separate analyses were conducted for visitation (
n
= 349, 15.4 ± 1.6 years, 58% female) and physical activity (
n
= 441, 15.4 ± 1.6 years, 59% female) using multilevel linear regression models.
Results
No significant associations were observed for frequency of visitation to a park (B = 0.86, 95% CI = − 0.26, 1.99), trails (B = 0.41, 95% CI = − 0.61, 1.44), beach/lake (B = − 0.44, 95% CI = − 1.46, 0.57), or sports facilities (B = 0.64, 95% CI = − 0.43, 1.70), nor for frequency of physical activity in their street (B = − 0.07, 95% CI = − 0.46, 0.31), local street/path (B = − 0.05, 95% CI = − 0.43, 0.33) or in a park (B = 0.23, 95% CI = − 0.14, 0.60) with adolescents’ social connectedness.
Conclusions
The findings did not support the hypothesis that visiting and being active in outdoor public recreation spaces are associated with adolescents’ social connectedness. Future research should consider the duration and context of outdoor public recreation space use (e.g., sports, socialising, relaxing alone) and whether different types and/or a combination of public spaces are more/less conducive to social connectedness.
Journal Article