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Bta-Mir-376A Targeting KLF15 Interferes with Adipogenesis Signaling Pathway to Promote Differentiation of Qinchuan Beef Cattle Preadipocytes

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Bta-Mir-376A Targeting KLF15 Interferes with Adipogenesis Signaling Pathway to Promote Differentiation of Qinchuan Beef Cattle Preadipocytes animals Article Bta-miR-376a Targeting KLF15 Interferes with Adipogenesis Signaling Pathway to Promote Differentiation of Qinchuan Beef Cattle Preadipocytes Xingyi Chen 1 , Sayed Haidar Abbas Raza 1 , Gong Cheng 1, Xinhao Ma 1, Jianfang Wang 1 and Linsen Zan 1,2,* 1 College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; [email protected] (X.C.); [email protected] (S.H.A.R.); [email protected] (G.C.); [email protected] (X.M.); [email protected] (J.W.) 2 National Beef Cattle Improvement Center, Northwest A&F University, Yangling 712100, China * Correspondence: [email protected]; Tel.: +86-29-87091923 Received: 15 October 2020; Accepted: 8 December 2020; Published: 10 December 2020 Simple Summary: Our study demonstrated that bta-miR-376a negatively regulates adipocyte proliferation and differentiation by targeting the adipogenesis signaling pathway and is thus a novel regulator of development in Qinchuan beef cattle. These findings contribute to a better understanding of adipogenesis regulated by miRNA and provide an important reference for studies on beef intramuscular fat. Abstract: Intramuscular fat (IMF) is a quality index associated with the taste and juiciness of meat. The deposition of IMF is affected by genetic and non-genetic factors, such as age, slaughter location, gender of the animal, and diet. Micro-ribonucleic acids (miRNA) are transcriptional regulators involved in adipogenesis, but the specific role of miR-376a in regulation of bovine adipocytes remains unknown. Our findings indicated that miR-376a was a potential negative regulator of bovine adipocyte differentiation. A bta-miR-376a mimic inhibited mRNA and protein expression of the marker genes, CDK1, CDK2, PCNA, C/EBPα, FAS, and PPAR γ, and significantly reduced ratios (%) of S-phase cells, the number of cells stained with 5-ethynyl-20-deoxyuridine, and adipocyte proliferation. Oil red O staining and triglyceride content analysis also confirmed that bta-miR-376a was involved in adipocyte differentiation. Luciferase activities confirmed that Krüppel-like transcription factor 15 (KLF15) was a direct target gene of bta-miR-376a, and that KLF15 was a key transcription factor in adipogenesis. Therefore, bta-miR-376a might be a target for increasing beef IMF. Keywords: Bta-miR-376a; KLF15; proliferation; adipocyte differentiation; beef quality 1. Introduction With the continuous growth of the world’s population and the improvement of living standards, insufficient production quality and quantity of animal-derived protein products have become the main problems facing world animal husbandry development. However, the study of fat deposition of Qinchuan cattle, a Chinese cattle breed which is famous for its fine texture of meat and relatively slow growth, will provide a new basis and ideas for beef cattle breed improvement, meat quality, and beef production [1]. The adipose tissue exerts a profound impact on physiology and pathophysiology [2]. It comprises various types of adipocytes, participates in the regulation of physiological and metabolic processes, and stores energy [3]. Adipose tissues play an important role in determination of meat quality. The main types of fat in mammals are intermuscular, intramuscular, subcutaneous, and peripheral. Animals 2020, 10, 2362; doi:10.3390/ani10122362 www.mdpi.com/journal/animals Animals 2020, 10, 2362 2 of 15 Among them, intramuscular fat (IMF) content is particularly important as a factor affecting the quality of beef: moderate content and uniform distribution of marbling can render meat tasty and juicy, whereas a low-fat content renders meat dry and dull [4]. However, increasing the amount of IMF without increasing the reserves of the other three types of fat is difficult [5]. Lipogenesis is a complex biological process that is closely related to energy and basic metabolism, and fat deposition involves a series of processes, including the proliferation, differentiation, and maturation of preadipocytes [6–8]. Adipogenesis is tightly controlled by a cascade of transcription factors [9]. MicroRNAs mediate gene silencing by guiding argonaute (Ago) protein to the target site of 3’UTR of mRNA, which plays an important role in gene regulation at the post-transcriptional level [10]. Most miRNAs exhibit high sequence conservation and tissue specificity [11]. MicroRNAs are involved in the regulation of adipocyte differentiation mainly via the following two mechanisms [12]: One mechanism involves signal pathways associated with adipocyte differentiation, including PPAR, MAPK, cAMP/PKA, and Wnt, whereas the other mechanism involves transcription factors such as PPARγ and C/EBP family members that regulate the expression of adipogenic genes such as FABP4, FASN, GLUT4, and other genes affect the differentiation of adipogenesis [3,6]. The miRNA miR-27a may play a key role in the differentiation of 3T3-L1 preadipocytes by inhibiting PPARγ [13]. MicroRNA-9 targets PNPLA3 through the AMPK pathway, thus inhibiting the differentiation of adipocytes in 3T3-L1 cells [14]. However, the effects of miRNAs related to the function and mechanism of adipogenesis require further investigation. A novel retinal preference for miR-376a, determined using a miR-microarray with altered expression in retinal diseases, has helped to elucidate the function of miRNA in normal and pathological retinas [15]. Current interest in miR-376a primarily focuses on cancer treatment [16–18]. The proliferation of osteosarcoma tumor cells is significantly inhibited by miR-127-3p and miR-376a-3p mimics [19]. The overexpression of miR-376a-3p inhibits the development of human umbilical vascular epithelial cells (HUVEC) by downregulating NRIP1 [20]. However, the mechanism by which miR-376a participates in the regulation of adipocyte differentiation remains unknown. Five miRNAs are differentially expressed with dynamic expression profiles in diabetic rat models of bone healing compared with controls, including miR-376a-3P [21]. Notably, miR-376a directly targets IGF1R to downregulate the IGF1R signaling pathway and affects melanoma cell migration [22]. These findings indicated that miR-376a played a key role in regulation of bovine adipogenesis. The findings of studies using bioinformatics online tools analyses have revealed the post-transcriptional regulation of genes relevant to adipogenesis via bta-miR-376a. Investigation of the regulation of bovine preadipocytes by bta-miR-376a may improve understanding of the molecular mechanism of bovine adipocytes and may profoundly impact meat quality. 2. Materials and Methods 2.1. Ethics Statement All animal procedures for experiments were approved by the Committee of Experimental Animal Management (EAMC) at Northwest A&F University, China (protocol number: NWAFUCAST2018–167). Moreover, the use of experimental animals was carried out in accordance with the rules and guidelines of the organization and government. 2.2. Isolation of Tissue Samples and Preadipocytes from Qinchuan Beef Cattle The tissue and cell samples used in the experiment in this study were collected from three 1-day-old healthy Qinchuan beef bulls bred from the National Beef Cattle Improvement Center of Northwest Agriculture and Forestry University (Yangling, China). Surgical instruments were used to collect tissue samples including heart, liver, spleen, lung, and muscle. The samples were placed in sterile, DNase- and RNase-free cell cryotubes and immediately frozen in liquid nitrogen. The samples were then stored in a freezer at 80 C for later use. − ◦ Animals 2020, 10, 2362 3 of 15 We used one-day-old healthy bulls to isolate the original bovine pre-adipocytes, removed the adipose tissue under aseptic conditions, washed with phosphate buffer saline(PBS) supplemented with 10% antibiotics (penicillin/streptomycin) 3 times, and then added I Collagenase digestion for 1–2 h in a 37 ◦C water bath shaker. Following digestion, we filtered with a cell sieve, and discarded the supernatant after centrifugation. Red blood cell lysate was added for lysis, and then an appropriate amount of DMEM-F12 (Gibco, Grand Island, NY, USA) medium containing 10% fetal bovine serum (FBS, Invitrogen, Waltham, MA, USA) was added to resuspend the cells for seeding for subsequent experiments. The cells used in this experiment were all the third generation cells after passage. 2.3. Cells Transfection In this study, bovine preadipocytes and HEK293A cells (Laboratory reservation) were cultured in DMEM-F12 and DMEM high-glucose medium (Gibco, Grand Island, NY, USA) and at 37 ◦C with 5% CO2, respectively. According to the transfection scheme of liposome 3000 (Invitrogen, Waltham, MA, USA) [8], bta-miR-376a mimic (50 nM), mimic NC (50 nm), si-KLF15 (100 nM), and the si-NC were transfected into bovine preadipocytes. The sequences of si-KLF15 are as follows: Sense 50-CUGGAGGAGAUUGAAGAGUTT-30 and antisense 50-ACUCUUCAAUCUCCUCCAGTT-30. The transfection concentration was 80%, 0.5 mm 3-Isobutyi-1-methylxanthine (IBMX), and 1 µm DXMS and 2 µm insulin were used to stimulate the differentiation of the fusion cells. Bta-miR-376a mimic and mimic NC used in this stage were purchased from RiboBio, Guangzhou, China, si-KLF15 and si-NC used in this stage were purchased from GenePharma, Shanghai, China. 2.4. Western Blotting Analysis Protein was obtained from bovine preadipocytes using a protein extraction kit, supplemented with PMSF (Beyotime, Shanghai, China), and protein concentration was quantified with the Quantitative Protein Kit (the BCA method) (APPLYGEN, Beijing, China). For Western
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