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Cold-Induced Adaptations to the Proteome of Mouse Subcutaneous White Adipose Tissue (scWAT) Reveal Proteins Relevant for Tissue Remodeling and Plasticity

ABSTRACT: White adipose tissue (WAT) is one of the most dynamic and plastic organs or tissues in the body, capable of expanding its mass in response to positive energy balance (either by proliferation of adipocytes - hyperphasia, or by increasing adipoycyte size - hypertrophy), developing inducible brown adipocytes through a process termed "browning", and changing its mitochondrial mass in response to stimuli such as cold exposure. Most notably, cold stimulation and release of norepinephrine from sympathetic nerve terminals is able to drive lipolysis in WAT (and thus smaller lipid droplet size and adipocyte size), as well as promote sympathetic nerve branching and increased neurite density, as well as development of pockets of browning around these neurite-dense regions of tissue. While several RNA-sequencing (including newer single cell RNAseq studies) have been done in WAT across situations of positive energy balance (such as high fat diet, obesity) or negative energy balance (such as cold stimulation of energy expenditure), very little work has been done to investigate changes to the adipose proteome while the tissue is actively remodeling. Here, we have carried out proteomics analysis on inguinal subcutaneous (sc)WAT of C57BL/6 mice after 24 or 72hrs of cold stimulation, a period during which UCP1 is actively turned on during the browning process. Through these data, we have found that numerous protein pathways changed by cold stimulation relate to tissue remodeling and plasticity, including changes to mitochondrial dynamics, tissue immune cells, and peripheral nerves.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Kristy L. Townsend

PROVIDER: MSV000087516 | MassIVE | Tue May 25 20:49:00 BST 2021

SECONDARY ACCESSION(S): PXD026262

REPOSITORIES: MassIVE

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Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes. Microarray analysis was performed on abdominal subcutaneous white adipose tissue samples from human type 2 diabetic patients before, and after 10 days of cold acclimation. A total of 14 samples, from 7 subjects, were used for the microarray analysis.

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Cold-Induced Adaptations to the Proteome of Mouse Subcutaneous White Adipose Tissue (scWAT) Reveal Proteins Relevant for Tissue Remodeling and Plasticity

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