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Principal Investigator: Armina-Lyn M Frederick
Organization: DARTMOUTH COLLEGE
Fiscal Year: 2024
Award: $45,446
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Metabolic dysregulation is the major preventable risk factor for leading causes of chronic
disease-related deaths. More specifically, chronic obesity is correlated with adipocyte hypertrophy
and hyperplasia, both of which may be circadianly regulated. All circadian clocks are cell-intrinsic,
and circadian oscillators that are tissue-specific control metabolic homeostasis by fine-tuning
nutrient utilization; adipose tissue responds to microenvironmental changes in a clock-dependent
manner. Thermogenic adipocytes can redirect energy away from ATP production during nutrient
excess by disrupting the electrochemical proton gradient, producing heat in a process called Non-
Shivering Thermogenesis (NST). Thermogenic adipocytes are sometimes capable of cell-
autonomously sensing ambient temperature and adopting a reversible thermogenic profile. The
circadian clock's importance in this thermogenic plasticity is not well understood, nor the cellular
decision to adopt this state. The objective of this work is to understand how circadian rhythms
affect adipocyte biology, especially thermogenic plasticity. To delineate the relationship between
the cellular circadian system and adipocyte biology in the absence of organismal cues, circadian
output will be characterized in Specific Aim 1 by transcriptionally profiling in vitro differentiated
adipocytes from inguinal adipose tissue over 3 circadian days with a 2-hour resolution via
RNAseq. In this way I will determine what aspects of adipocyte biology and environmental stimuli
can be influenced by time-of-day. Though multilocularity and mitochondrial abundance are not
indicators of thermogenic potential per se, these two organelles are intricately involved in NST.
To extend the hypothesis that thermogenic plasticity is clock-controlled, I will use quantitative
fluorescence live cell microscopy to characterize lipid droplet and mitochondrial spatial patterning
and thereby describe organelle morphology as a function of circadian time. In Specific Aim 2 I
will determine the cell-autonomous clock’s role in heat production, the quintessential component
of thermogenesis, using infrared thermal imaging to identify rhythms in heat production (1) during
a state of decreased bioenergetic efficiency via uncoupling with BAM15 and (2) by suppressing
UCP1 with purine nucleotides. The long-term goal of this proposal is to determine the clock’s role
in regulating thermogenesis. Findings from this study will increase our understanding of clock-
controlled energy metabolism and adipocyte dysfunction, advancing our understanding of the
non-linear association between weight, energy expenditure and risk in chronic disease.
Terms: <Address><Adipocytes><Adipose Cell><Adipose tissue><Adopted><Affect><Autoregulation><BAT uncoupling protein><Binding><Bioenergetics><Biological Clocks><Biology><Body Tissues><Bypass><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cessation of life><Chronic><Chronic Disease><Chronic Illness><Circadian Rhythms><Confocal Microscopy><Coupled><Creatine><Cues><Cyclicity><Data><Death><Differentiation in cell culture><Disease><Disorder><Dysfunction><Elements><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><Epidemic><Fat Cells><Fatty Tissue><Feedback><Fluorescence><Functional disorder><Futile Cycling><Futile Cyclings><Futile Substrate Cycling><Futile Substrate Cyclings><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genes><Genetic Transcription><Genomics><Goals><H+ element><Heat Production><Homeostasis><Hour><Human Figure><Human body><Hydrogen Ions><Hyperplasia><Hyperplastic><Hypertrophy><Image><Immunoblotting><In vitro cell differentiation><Intermediary Metabolism><Learning><Light><Link><Lipids><Lipocytes><Mature Lipocyte><Mature fat cell><Mediating><Messenger RNA><Metabolic><Metabolic Control><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Mitochondria><Molecular><Molecular Interaction><Monitor><Morphology><Murine><Mus><Nutrient><Nyctohemeral Rhythm><Obesity><Oligomycins><Organelles><Output><Pathway interactions><Pattern><Periodicity><Phase><Phenotype><Photoradiation><Physiologic><Physiological><Physiological Homeostasis><Physiology><Physiopathology><Process><Production><Protons><Purine Nucleotides><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Research><Resolution><Respiration><Rhythmicity><Risk><Risk Factors><Role><Sight><Sleep Wake Cycle><Stimulus><Subcellular Process><System><Systems Biology><Temperature><Testing><Thermogenesis><Time><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Twenty-Four Hour Rhythm><Vision><Weight><Western Blotting><Western Immunoblotting><Work><adipocyte biology><adipocyte development><adipocyte differentiation><adipose><adiposity><analyze gene expression><bio-informatics tool><bioinformatics tool><body clock><brown adipose tissue uncoupling protein><cell biology><cell type><chronic disorder><circadian><circadian biology><circadian clock><circadian pacemaker><circadian process><circadian regulation><corpulence><daily biorhythm><differentiation in culture><differentiation in vitro><fat metabolism><gene expression analysis><gene expression assay><glucose metabolism><imaging><in vitro cellular differentiation><internal clock><lipid metabolism><live cell microscopy><luminescence><mRNA><mitochondrial><pathophysiology><pathway><postmitotic><protein blotting><resolutions><respiratory mechanism><social role><thermogenin><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing><uncoupling protein 1><visual function><weights><white adipose tissue><yellow adipose tissue>