Loss of glucagon signaling alters white adipose tissue browning

Abstract

Various endocrine factors contribute to cold‐induced white adipose tissue (WAT) browning, but glucagon has largely been ignored. The purpose of the current investigation was to determine if glucagon was required for the effects of cold on WAT browning. Utilizing whole‐body glucagon receptor knockout (Gcgr−/−) mice and their wild‐type (WT) littermate controls, we examined the response of inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) to an acute (48 h) cold stress or challenge with the β3‐adrenergic agonist CL316,243. The effects of glucagon alone on the induction of thermogenic genes in adipose tissue from C57BL6/J mice were also examined. Gcgr−/− mice displayed modest increases in indices of browning at room temperature while displaying a blunted induction of Ucp1, Cidea, and Ffg21 mRNA expression in iWAT following cold exposure. Similarly, cold induced increases in mitochondrial DNA copy number, and the protein content of mitochondrial respiratory chain complexes, UCP1, and PGC1α were attenuated in iWAT from Gcgr−/− mice. In BAT, the induction of thermogenic markers following cold exposure was reduced, but the effect was less pronounced than in iWAT. Glucagon treatment increased the expression of thermogenic genes in both iWAT and BAT of C57BL6/J mice. In response to CL316,243, circulating fatty acids, glycerol, and the phosphorylation of hormone‐sensitive lipase were attenuated in iWAT of Gcgr−/− mice. We provide evidence that glucagon is sufficient for the induction of thermogenic genes in iWAT, and the absence of intact glucagon signaling blunts the cold‐induced browning of WAT, possibly due, in part, to impaired adrenergic signaling.—Townsend, L. K., Medak, K. D., Knuth, C. M., Peppier, W. T., Charron, M. J., Wright, D. C. Loss of glucagon signaling alters white adipose tissue browning. FASEB J. 33, 4824–4835 (2019). http://www.f asebj.org

Epinephrine responsiveness is reduced in livers from trained mice

“…Ponceau S (cat no. P7170; Sigma Aldrich) staining or a housekeeping protein (Vinculin or GAPDH) were used as a loading control (Townsend et al, ). Phosphorylated and total protein were expressed relative to their within‐gel loading control, then phosphorylated proteins were normalized to total protein (i.e., phosphor/total).…”

“…15596018; ThermoFisher Scientific) and RNA was extracted using Bio Basic EZ-10 Spin Column Total RNA Miniprep Super Kits (cat no. BS784; Bio Basic) as described previously (Frendo-Cumbo et al, 2016;Peppler, Townsend, Knuth, Foster, & Wright, 2018;Townsend et al, 2019). Synthesis of cDNA was completed using Superscript II (cat no.…”

Exercise and Dairy Protein have Distinct Effects on Indices of Liver and Systemic Lipid Metabolism

“…Liver homogenization, protein extraction, and Western blotting were carried out as described in detail previously . Primary antibodies were purchased from AbCam for citrate synthase (CS) (#ab129095), ubiquinol‐cytochrome C reductase core protein 1 (CORE1) (#ab1102520), cytochrome C oxidase subunit IV (COXIV) (#ab16056), and stearoyl‐CoA desaturase 1 (SCD1; #ab19862).…”

Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network

“…Beyond suppressing hyperglycemia, disruption of GCGR also leads to increased insulin sensitivity, hypoglycemia, hyperglucagonemia, hyperaminoacidemia, increased plasma LDL, increased GLP-1 and FGF21 levels, decreased adiposity, and hyperplasia of pancreatic α-cells in mouse models [6,[14][15][16]. The disruption of GCGR by antagonism or gene knockout in animal models also causes dysregulation of other metabolic processes, including cholesterol absorption, fatty acid utilization, white adipose tissue browning, and bile acid metabolism [17][18][19][20]. In humans, patients with GCGR mutations develop a syndrome known as Mahvash disease, characterized by hypercalcemia, hyperglucagonemia, and α-cell hyperplasia [21][22][23][24].…”