Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats

Abstract

Ϫ/Ϫ mice have decreased hepatic expression of gluconeogenic enzymes and a reduction in the rate of endogenous glucose production (EGP). We sought to determine whether decreasing hepatic and adipose SRC1 expression in normal adult rats would alter glucose homeostasis and insulin action. Regular chow-fed and high-fat-fed male Sprage-Dawley rats were treated with an antisense oligonucleotide (ASO) against SRC1 or a control ASO for 4 wk, followed by metabolic assessments. SRC1 ASO did not alter basal EGP or expression of gluconeogenic enzymes. Instead, SRC1 ASO increased insulin-stimulated whole body glucose disposal by ϳ30%, which was attributable largely to an increase in insulinstimulated muscle glucose uptake. This was associated with an approximately sevenfold increase in adipose expression of lipocalintype prostaglandin D 2 synthase, a previously reported regulator of insulin sensitivity, and an approximately 70% increase in plasma PGD 2 concentration. Muscle insulin signaling, AMPK activation, and tissue perfusion were unchanged. Although GLUT4 content was unchanged, SRC1 ASO increased the cleavage of tether-containing UBX domain for GLUT4, a regulator of GLUT4 translocation. These studies point to a novel role of adipose SRC1 as a regulator of insulin-stimulated muscle glucose uptake. insulin resistance; glucose transporter type 4; skeletal muscle; white adipose tissue GLUCOSE HOMEOSTASIS REQUIRES THE COMPLEX COORDINATION of cellular and molecular pathways in multiple tissues. In many instances, these pathways collate hormonal and metabolic cues to regulate transcription factors that alter the expression of genes encoding key metabolic enzymes. The activity of transcription factors is regulated further by transcriptional coactivators and corepressors. The three members of the p160 steroid coactivator receptor family, the steroid receptor coactivator 1 (SRC1 or NcoA-1), the transcriptional intermediary factor 2 (TIF2, SRC2, GRIP1, or NCOA2), and steroid receptor coactivator 3 (SRC3, p/CIP, AIB1, ACTR, RAC3, or TRAM-1) have all been shown to control energy balance through their interactions with many transcription factors, including nuclear receptors (14,16,18,22). The SRC1 family has also been implicated in many other physiological processes, including reproduction, cancer, and immunity (22,27,42,49,50).A significant body of work has shown that SRC1 is important for the tissue-specific activation of progesterone and estrogen receptors (1,16,42). Additionally, studies using the SRC1 global knockout mice have shown that SRC1 is required for uterine growth and function, prostate development, mammary gland growth and elongation, brain development and function, and metabolism (20,23,24,28,31,49,50,52). SRC1 Ϫ/Ϫ mice also have features of thyroid hormone resistance, with evidence that SRC1 is critical for proper activation of the thyroid hormone receptor-␤ (48). SRC1 Ϫ/Ϫ mice have impairment in brown adipose tissue (BAT) function that makes them prone to weight gain potentially through decreased activation of PGC-1...

Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

“…TUG may tether vesicles stably, or constrain a cycle of budding and fusion, to trap GSVs at the Golgi matrix. To mobilize these vesicles, insulin triggers site-specific endoproteolytic cleavage of TUG 5 , 16 – 19 . The N-terminal cleavage product is a ubiquitin-like modifier, called TUGUL (“TUG Ubiquitin-Like”).…”

Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

“…Gastrocnemius muscles, liver tissues, BAT or WAT were extracted from mice and preincubated for 2 h at 30°C in Krebs-Ringer bicarbonate HEPES buffer (KRBH) containing (mM): 129 NaCl, 5 NaHCO 3 , 4.8 KCl, 1.2 KH 2 PO 4 , 1.2 MgSO 4 , 2.5 CaCl 2 , 2.8 glucose, 10 HEPES, and 0.1% BSA at pH 7.4. For ex vivo glucose uptake assay, tissues were incubated for 2 h with insulin 60 mU/mL followed by measurement of 2-deoxy-[ 3 H]-glucose uptake as described previously (54). For dose-dependent analysis of glycolysis and lipolysis in tissues ex vivo, tissues were incubated for 15 min with EPI at 0, 1, 5, 10, or 50μg/mL followed by measurement of lactic acid, glycerol or NEFA contents in culture medium.…”