Adipocyte to neuron signaling in thermogenic programming of white adipose tissue

白色脂肪组织产热编程中的脂肪细胞至神经元信号传导

• 批准号: 10547782
• 负责人: MICHAEL P CZECH
• 金额: $ 58.29万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547782
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Address; Adipocytes; Adipose tissue; Antibodies; Appearance; Brown Fat; Caloric Restriction; Cellular Structures; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Cyclic AMP; Data; Denervation; Development; Energy Metabolism; Enzymes; Exercise; Fasting; Fatty Acids; Fatty acid glycerol esters; Fatty-acid synthase; Goals; Health; Histone Acetylation; Homeostasis; Human; Implant; In Vitro; Kinetics; Knockout Mice; Knowledge; Laboratories; Lentivirus; Link; Malonyl Coenzyme A; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Neuregulins; Neurites; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PC12 Cells; Palmitoyl Coenzyme A; Paracrine Communication; Pathway interactions; Physiological; Proteins; Publishing; Recombinant Proteins; Resolution; Role; Signal Pathway; Signal Transduction; Solid; Technology; Testing; Time; Transcriptional Regulation; Transplantation; Tyrosine 3-Monooxygenase; adipocyte differentiation; blood glucose regulation; experimental study; fat burning; fatty acid oxidation; glucose tolerance; implantation; improved; in vivo; insulin sensitivity; lipid biosynthesis; nanoparticle; nerve supply; neuregulin-4; neuronal growth; neurotransmission; neurotrophic factor; new technology; novel; novel therapeutic intervention; palmitoylation; response; small hairpin RNA; stem cells

Abstract The overarching long term goal of our laboratory is to understand and exploit how adipose tissues exert powerful control over whole body glucose tolerance and insulin sensitivity. Small amounts of mouse brown (BAT) or human “Beige” adipocytes transplanted into recipient mice can improve glucose homeostasis, highlighting the importance of understanding mechanisms of adipose browning. Based on the knowledge that intermediates of the de novo lipogenesis (DNL) pathway display potent signaling functions (e.g., Acetyl CoA as substrate for histone acetylation, transcriptional regulation) and that adipocyte DNL is highly regulated by obesity, fasting, cold exposure, and exercise, we hypothesize that adipocyte DNL is a major regulatory node in metabolism. We aim to interrogate this concept by perturbing this DNL pathway through selective KO of DNL enzymes ATP citrate lyase (ACLY) and fatty acid synthase (FASN). Our preliminary data encourage this approach by revealing that FASN KO upregulates adipocyte neurotrophic factor Neuregulin 4 (Nrg4) and enhances expansion of sWAT sympathetic neurons (SNS), even at thermo-neutrality (30C). Thus, DNL metabolites (Acetyl CoA, Malonyl CoA) or DNL product (Palmitoyl CoA) appear to be intimately linked to controlling adipose SNS activity, adipose energy expenditure and whole body glucose homeostasis. Based on these data, this project seeks to determine the cellular and molecular mechanisms whereby adipocytes can signal to localized SNS neurons and promote the development of Beige adipocytes in sWAT. Aim 1 will determine whether Beige adipocytes in iAdFASNKO mice are derived by direct “conversion” of mature white to beige adipocytes OR by paracrine signaling to induce differentiation of progenitor cells to Beige adipocytes. To address underlying mechanisms, Aim 2 will determine whether Nrg4 (and Negr1, which may also be upregulated) mediates the effect of FASN-depleted adipocytes to cause expansion of the SNS in vivo. This Aim is based on exciting preliminary data showing that conditioned media from such adipocytes cause marked neurite outgrowth in PC-12 neurons in vitro, which is inhibited by Nrg4 silencing. New technology we developed will be used to delete adipocyte Nrg4 and Negr1 using CRISPR-based nanoparticles prior to implantation into recipient mice and analysis of their effects on SNS innervation. Finally, Aim 3 tests whether adipocyte DNL intermediate metabolites Acetyl CoA/Malonyl CoA in iAdFASNKO mice initiate signaling to cause Nrg4 expression and SNS expansion. These adipocyte metabolites in iAdFASNKO mice, and their acetylation and malonylation of cellular proteins, will be reversed by KO of ATP citrate Lyase (ACLY), which generates the Acetyl CoA, in double KO mice. Identifying the DNL intermediates that modulate adipocyte function will enable defining their underlying mechanisms. Together, these experiments have high potential to define novel signaling pathways driven by DNL metabolites that regulate adipose browning and new therapeutic strategies for type 2 diabetes.

摘要