Endocrinol Metab.  2022 Jun;37(3):552-557. 10.3803/EnM.2022.1421.

Sestrin2 Regulates Beneficial β3-Adrenergic Receptor-Mediated Effects Observed in Inguinal White Adipose Tissue and Soleus Muscle

Affiliations
  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
  • 2BK21 Graduate Program, Department of Biomedical Sciences and Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Abstract

Sestrin2, a well-known adenosine monophosphate-activated protein kinase (AMPK) regulator, plays a protective role against metabolic stress. The β3-adrenergic receptor (β3AR) induces fat browning and inhibits muscle atrophy in an AMPK-dependent manner. However, no prior research has examined the relationship of sestrin2 with β3AR in body composition changes. In this study, CL 316,243 (CL), a β3AR agonist, was administered to wild-type and sestrin2-knockout (KO) mice for 2 weeks, and fat and muscle tissues were harvested. CL induced AMPK phosphorylation, expression of brown-fat markers, and mitochondrial biogenesis, which resulted in the reduction of lipid droplet size in inguinal white adipose tissue (iWAT). These effects were not observed in sestrin2-KO mice. In CL-treated soleus muscle, sestrin2-KO was related to decreased myogenic gene expression and increased levels of muscle atrophy-related molecules. Our results suggest that sestrin2 is associated with beneficial β3AR-mediated changes in body composition, especially in iWAT and in the soleus.

Keyword

Sestrin2 protein, mouse; Adrenergic beta-3 receptor agonists; Adipose tissue, brown; Muscle development; Muscular atrophy

Figure

  • Fig. 1. Sestrin2 deficiency reduces CL 316,243 (CL)-mediated fat browning in inguinal white adipose tissue (iWAT), but not in epididymal white adipose tissue (eWAT). (A) Rectal temperature changes during 1 hour under vehicle (Veh) or CL treatment. (B) Fat images and weight (per body weight). The side length of a dotted square is 1.2 cm. (C) Western blots of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α), uncoupling protein-1 (UCP-1), and sestrin2. (D, E) Quantitative polymerase chain reaction (PCR) of UCP-1, PR domain containing 16 (PRMD16), elongation of very long chain fatty acids protein 3 (Elovl3), cell death activator CIDE-A (Cidea), mitochondrial transcription factor A (Tfam), and nuclear respiratory factor 1 (NRF1). (F) Ratio of mitochondrial DNA (mtDNA) to genomic DNA (gDNA). (G) Hematoxylin and eosin (H&E) staining; the lipid droplet (LD) diameter was measured from five views for each tissue using ImageJ software. The length of a scale bar is 20 μm. (H) Western blot of hormone-sensitive lipase (HSL) abundance. (I) Measurements of serum free fatty acid (FFA) levels. All graphs were obtained from six mice per group. Error bars represent mean±standard deviation. KO, knockout. aP<0.05 vs. the wild-type (WT)-Veh group; bP<0.05 vs. the WT-CL group, as analyzed with analysis of variance (ANOVA) followed by the Tukey-Kramer test.

  • Fig. 2. Sestrin2 deficiency regulates myogenic and atrophic-related events under CL 316,243 (CL) treatment in the soleus, but not in the extensor digitorum longus (EDL). (A) Muscle images and weight (per body weight). The side length of the dotted square is 1.2 cm. (B) Western blots of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), p38, and sestrin2. (C) Quantitative polymerase chain reaction (PCR) of myoblast determination protein 1 (MyoD), myocyte enhancer factor 2C (Mef2c), and myogenic factor 5 (Myf5). (D) Western blot of phosphorylated forkhead box O1 (FOXO1), atrogin1, and muscle ring-finger protein-1 (MurF1). All graphs were obtained from six mice per group. Error bars represent mean±standard deviation. Q, quadriceps; TA, tibialis anterior; Gas, gastrocnemius; Sol, soleus. aP<0.05 vs. the wild-type (WT)-vehicle (Veh) group; bP<0.05 vs. the WT-CL group, as analyzed with analysis of variance (ANOVA) followed by the Tukey-Kramer test.


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