Essential Role of Granulosa Cell Glucose and Lipid Metabolism on Oocytes and the Potential Metabolic Imbalance in Polycystic Ovary Syndrome

Abstract

Granulosa cells are crucial for the establishment and maintenance of bidirectional communication among oocytes. Various intercellular material exchange modes, including paracrine and gap junction, are used between them to achieve the efficient delivery of granulosa cell structural components, energy substrates, and signaling molecules to oocytes. Glucose metabolism and lipid metabolism are two basic energy metabolism pathways in granulosa cells; these are involved in the normal development of oocytes. Pyruvate, produced by granulosa cell glycolysis, is an important energy substrate for oocyte development. Granulosa cells regulate changes in intrafollicular hormone levels through the processing of steroid hormones to control the development process of oocytes. This article reviews the material exchange between oocytes and granulosa cells and expounds the significance of granulosa cells in the development of oocytes through both glucose metabolism and lipid metabolism. In addition, we discuss the effects of glucose and lipid metabolism on oocytes under pathological conditions and explore its relationship to polycystic ovary syndrome (PCOS). A series of changes were found in the endogenous molecules and ncRNAs that are related to glucose and lipid metabolism in granulosa cells under PCOS conditions. These findings provide a new therapeutic target for patients with PCOS; additionally, there is potential for improving the fertility of patients with PCOS and the clinical outcomes of assisted reproduction.

Keywords: PCOS; glucose metabolism; granulosa cells; lipid metabolism; oocytes.

Figure 1

Paracrine-mediated signaling between granulosa cells and oocytes. Oocytes mainly secrete the paracrine factors BMP15 and GDF9. BMP binds to a dimer composed of the TGFβ receptor ALK6/BMPRII and activates SMAD1,5,8. GDF9 binds to a dimer composed of ALK5/BMPR8 and activates SMAD2,3. SMAD controls a variety of biological processes by regulating gene transcription. These include the upregulation of PTX3 and HAS2 expression to promote hyaluronan synthesis and COC expansion; inhibition of CX43 to reduce TZP; inhibition of StAR to reduce progesterone production; regulation of apoptosis-related genes such as BAX, CASP9, TP53, and BCL2 to achieve apoptosis inhibition; and regulation of granulosa cell KITL1 protein levels. KITL is a granulosa cell paracrine factor that activates KIT in response to FSH stimulation and activates the P13K-AKT-FKHRL1 pathway to regulate oocyte survival, activation, and apoptosis. BMP15 promotes the expression of KITL1/2 and is inhibited by high concentrations of KITL. GDF9 inhibits KITL expression. BMP15—bone morphogenetic protein 15; GDF9—growth differentiation factor 9; SMAD—Sma- and Mad-related proteins; PTX3—pentraxin 3; HAS2—hyaluronan synthase 2; CX43—connexin 43; StAR—steroidogenic acute regulatory protein; KITL—stem cell factor (also known as Kit ligand); FSH—follicle-stimulating hormone; FKHRL1—Forkhead box protein O1 (FOXO1).

Figure 2

There are three main transport modes for substances at the tip of TZPs: gap junctions, adhesion junctions, and extracellular vesicle transport. Gap junctions enable the efficient transport of substances such as pyruvate, amino acids, cAMP, and cGMP via Connexin. Adhesion junctions mainly include several kinds of E-cadherin/N-cadherin, Notch/Jagged, and KITL/KIT, which are mainly used for stabilizing TZPs structure and intercellular information exchange. Extracellular vesicles are mainly used for macromolecule transport. TZPs are simultaneously regulated by the endogenous granulosa cell signal Myo10; the oocyte signal GDF9; and the extracellular signals EGF, PTK2, and EPAB. TZPs—transzonal projections; GDF9—growth differentiation factor 9; EGF—epidermal growth factor; Myo10—myosin X; LH—luteinizing hormone; EVs—extracellular vesicles; PTK2—proline-rich tyrosine kinase 2; EPAB—eukaryotic poly(A)-binding protein; cAMP—cyclic adenosine monophosphate; cGMP—cyclic guanosine monophosphate.

Figure 3

Effects of granulosa cell glucose and lipid metabolism on oocytes. Glucose metabolism in granulosa cells mainly includes glycolysis, the pentose phosphate pathway, and the hexosamine biosynthesis pathway. Granulosa cells deliver energy precursors such as pyruvate and lactate to granulosa cells through glycolysis. GSH and NADPH are supplied to oocytes through the pentose phosphate pathway, which contributes to oxidative stress inhibition and mitotic regulation. Hyaluronic acid dissection is stabilized through the hexosamine biosynthesis pathway to maintain oocyte energy supply. Granulosa cell lipid metabolism is mainly divided into fatty acid metabolism and steroid metabolism. For fatty acid metabolism, granulosa cell β-oxidation products and oocyte meiosis-related factors promote each other to meet the meiotic energy supply. For steroid metabolism, granulosa cells can metabolize estrogen, progesterone, cortisol, and other hormones to achieve oocyte growth regulation. MCG—mural granulosa cell; PFK—phosphofructokinase; PDK—pyruvate dehydrogenase kinase; PDH—pyruvate dehydrogenase; HIF—hypoxia-inducible factor; GSH—glutathione; GSSH—glutathione disulfide; ROS—reactive oxygen species; NADPH—nicotinamide adenine dinucleotide phosphate; TCA—tricarboxylic acid cycle; OXPHOS—oxidative phosphorylation; HBP—hexosamine biosynthetic pathway; LDHA—lactate dehydrogenase A; LDHB—lactate dehydrogenase B; PRPP—phosphoribosyl pyrophosphate; Sirtuin—silent information regulator 2 (Sir2) proteins; GLUT—glucose transporter; MCT—monocarboxylate transporter; PRKA—protein kinase A; ACAC—acetyl-CoA carboxylase; CPT1—carnitine palmitoyltransferase 1; FFA—free fatty acid; PDE—phosphodiesterase; HSL—hormone-sensitive lipase; CGI-58—comparative gene identification 58; ATGL—adipose triglyceride lipase; PLIN2—perilipin 2; HDL—high-density lipoprotein.

Figure 4

The ncRNA involved in abnormal GCs glucose and lipid metabolism in PCOS. PCOS patients show altered levels of several ncRNAs. miR-196-5p and Inc-CCNL-3:1 affected glucose metabolism in GCs, mainly including glucose uptake and insulin resistance. miR-93, miR-21, miR-145, miR-335-5P, miR-29a, miR-320a, miR-323-3p, miR-27a-3p, and miR-196-5p affect lipid metabolism in GCs, mainly including the synthesis and secretion of multiple steroid hormones. The effects of miR-27a-3p and miR-196-5p on glucose and lipid metabolism have only been identified in mice models and have not been clinically confirmed. GCs—granulosa cells.