Biology subjects

Clark, J. P.

Publications and source records attributed to Clark, J. P..

3 recordsLinked to original sources

bioRxiv2025

Caloric restriction reprograms adipose tissues in rhesus monkeys

Caloric restriction (CR) is a dietary intervention that delays the onset of age-related diseases and enhances survival in diverse organisms, and although changes in adipose tissues have been implicated in the beneficial effects of CR the molecular details are unknown. Here we show shared and depot-specific adaptations to life-long CR in subcutaneous and visceral adipose depots taken from advanced age male rhesus monkeys. Differential gene expression and pathway analysis identified key differences between the depots in metabolic, immune, and inflammatory pathways. In response to CR, RNA processing and proteostasis-related pathways were enriched in both depots but changes in metabolic, growth, and inflammatory pathways were depot-specific. Commonalities and differences that distinguish adipose depots are shared among monkeys and humans and the response to CR is highly conserved. These data reveal depot-specificity in adipose tissue adaptation that likely reflects differences in function and contribution to age-related disease vulnerability. In BriefRhesus monkey adipose tissues are highly responsive to long-term caloric restriction, although the response is depot-specific. Shared features include proteostasis and RNA processing pathways, whereas metabolic pathways, alterations in processes influenced by growth signaling, and changes in exon usage were depot-specific. The impact of CR on subcutaneous adipose tissue is highly conserved between monkeys and humans. HighlightsO_LIAt the transcript level, SAT and VAT taken from the same animals show modest specialization, primarily in metabolic and immune pathways. C_LIO_LIThe transcriptome of SAT is more responsive to CR than that of VAT, with depot-specific differences in metabolic adaptation and cell type composition. C_LIO_LIRNA processing pathways are engaged by CR and transcript isoforms are enriched in both depots, but differential exon usage is limited to SAT. C_LIO_LIAdipose reprogramming is linked to CR induced differences in body composition and systemic indices of health. C_LIO_LIThe impact of CR on subcutaneous adipose tissue is highly similar between monkeys and humans. C_LI

genomics↗

bioRxiv2024

Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway dependent AMPK activation.

Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation.

neuroscience↗

bioRxiv2023

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

cell biology↗