Carlos Henrique Grossi Sponton

@fmrp.usp.br

Professor of Physiology - Department of Physiology - Ribeirão Preto Medical School
University of São Paulo

Carlos Henrique Grossi Sponton


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https://researchid.co/csponton

RESEARCH, TEACHING, or OTHER INTERESTS

Physiology, Molecular Biology
27

Scopus Publications

Scopus Publications

  • Metabolic sexual dimorphism in hypothalamic Fezf1 neuron-specific BDNF knockout
    Dayana Cabral-da-Silva, Ariane M. Zanesco, Fernando Valdivieso-Rivera, Ana L. Gallo-Ferraz, Marcela R. Simões, Bruna Bombassaro, Carlos H. Sponton, Licio A. Velloso
    Biology of Sex Differences, 2025
    Background Brain-derived neurotrophic factor (BDNF) is highly expressed in the hypothalamus where it exerts regulatory functions over neurogenesis, reproduction, energy balance, and metabolism. Analyzing a hypothalamic single-nucleus transcriptomic, we identified Fezf1 ventromedial hypothalamic (VMH) neurons as an important source of BDNF. During development, Fezf1 neurons are involved in the organization of the olfactory bulb, and mutations on this gene are responsible for Kallmann syndrome; however, in adult life, little is known about the functions of Fezf1 neurons. Methods In this study, we aimed at providing advance in the characterization of Fezf1 neurons and exploring the role of Fezf1-BDNF in the regulation of the metabolic phenotype of mice. Hypothalamic immunofluorescence was employed to determine the distribution and projections of Fezf1 neurons. Mice with a Fezf1-specific knockout of BDNF were constructed and used in the determination of the metabolic phenotype. Results Using a Cre-Lox system to express mCherry specifically in Fezf1 neurons of the VMH, we identified projections to the dorsomedial hypothalamus and the zona incerta, regions involved in metabolic control and motor activity, respectively. The Fezf1-specific knockout of BDNF resulted in increased cold tolerance in males, and protection against diet-induced obesity due to a reduction in food intake and increased spontaneous ambulatory activity in females. This was accompanied by protection against glucose intolerance, and increased insulin sensitivity, in females. Conclusions Thus, the present work provides advance in the understanding of the biology of VMH Fezf1 neurons, revealing the details of its distribution and projections, and demonstrating that the expression of BDNF in these neurons is involved, according to a sexual dimorphic pattern, in the regulation of metabolic function. In addition, this is the first evidence that, in a specific hypothalamic cell population, BDNF may have a detrimental rather than positive role in the regulation of systemic metabolism.
  • Bidirectional shifts in Pm20d1 expression impact thermogenesis and metabolism
    Marcela R. Simoes, Ana L. Gallo-Ferraz, Bruna Bombassaro, Fernando Valdivieso-Rivera, Guilherme A. S. Nogueira, Milena Monfort-Pires, Marcos Vinicius da Cruz, Ariane M. Zanesco, Nayra Fernanda-Oliveira, Leonardo Reis Silveira, Roger F. Castilho, Carlos H. Sponton, Licio A. Velloso
    Molecular Medicine, 2025
    Background Peptidase M20 domain containing 1 (PM20D1) is a secreted N-fatty acyl amino synthase and hydrolase that controls tissue and blood levels of N-fatty acyl amino acids. In brown adipocytes, N-fatty acyl amino acids bind to mitochondria and act as uncouplers of mitochondria, independent of UCP1. Interventions aimed at increasing or inhibiting PM20D1 expression considerably impact energy balance and metabolism; however, little is known about naturally occurring variants of the PM20D1/Pm20d1 gene and their impact on phenotype. Methods In vivo, gene expression of Pm20d1 in BALB/c, C57BL/6, and Ucp1 KO in brown adipose tissue and other metabolic tissues was measured. In vitro, transcriptional activity of Pm20d1 and brown adipocytes’ oxygen consumption in primary culture were assessed. Human PM20D1 circulating levels were quantified. In silico analysis of the Pm20d1 gene sequencing and human polymorphisms associated with PM20D1 was performed. Results Here, we identified a gain-of-function variant in the Pm20d1 promoter region present in BALB/c mice and absent in C57BL/6 mice. The presence of this variant is accompanied by increased expression of Pm20d1 in brown and white adipose tissues, muscle, liver, and hypothalamus; moreover, it leads to increased cold tolerance and UCP1-independent brown adipose tissue mitochondrial respiration. Inhibition of Pm20d1 in brown adipose tissue results in defective cold tolerance in BALB/c, whereas the brown adipose tissue overexpression of Pm20d1 results in increased cold tolerance in C57BL/6 mice. In humans, variants of the PM20D1 gene are associated with changes in body mass index, whereas at least one variant in the promoter region is associated with increased body mass index and metabolic syndrome. Conclusion Thus, PM20D1 plays a bidirectional role in regulating thermogenesis and body mass, and, at least in part, variants in the promoter region can partially explain the differences in PM20D1 expression and its impact on the metabolic phenotype.
  • Balb/c mice are protected from glucose and acute cold intolerance
    Marcela R. Simoes, Bruna Bombassaro, Ana Luisa Gallo-Ferraz, Pedro A.S. Nogueira, Milena Monfort-Pires, Ariane M. Zanesco, Fernando Valdivieso-Rivera, Guilherme A.S. Nogueira, Carlos H. Sponton, Roger F. Castilho, Licio A. Velloso
    Biochimica Et Biophysica Acta Molecular Basis of Disease, 2025
  • IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat
    Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt
    EMBO Journal, 2024
    While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called “reverse mode” of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
  • Editorial: Mechanistic and physiological implications of insulin resistance in metabolic diseases
    Hilda E. Ghadieh, Marco Infante, Carlos H. Sponton
    Frontiers in Endocrinology, 2024
    The present Research Topic entitled "Mechanistic and Physiological Implications of Insulin Resistance in Metabolic Diseases" aimed to collect the most updated reports in the field of insulin resistance (IR) and metabolic syndrome (MetS). Since the pathophysiological mechanisms of IR remain only partly understood, we herein present a comprehensive understanding of insulin signaling regulation by providing new insights into the impact of altered insulin action on metabolic processes. A cross-sectional study [1] investigated the relationship between triglyceride glucose-body mass index (TyG-BMI) and testosterone levels in adult males, considering TyG-BMI as a novel marker of IR. Using data from the NHANES 2011-2016, the analysis revealed a negative association between TyG-BMI and circulating testosterone levels, even after adjusting for confounders. Testosterone levels were significantly lower in the groups with higher TyG-BMI values. Thus, the ability of the TyG-BMI index to predict testosterone deficiency surpassed that of both the homeostatic model assessment for insulin resistance (HOMA-IR) index and the triglyceride-glucose (TyG) index. Another cross-sectional study [2] explored a practical approach for diagnosing metabolic dysfunctionassociated fatty liver disease (MAFLD). While the exact pathophysiology of MAFLD remains uncertain, IR is a main contributor. Analyzing databases of regular health check-up examinations, researchers investigated the association between MAFLD and four indices, namely: TyG index, fatty liver index (FLI), and modified TyG-related parameters such as TyG-BMI and TyG-waist circumference (TyG-WC). Authors found that modified TyG-related parameters were strongly 36 associated with MAFLD, showing an even predictive power as compared to the TyG index. 37Therefore, modified TyG indices may offer reliable MAFLD prediction daily clinical 38 practice, simplifying diagnosis and improving patient care in real-world settings. 39 40A meta-analysis [3] A retrospective cross-sectional study [4] explored the relationship between IR, hyperinsulinemia, and 51 bone mineral density (BMD) in 437 non-diabetic postmenopausal women. Results showed that 52 elevated HOMA-IR and fasting insulin levels were associated with increased BMD and decreased 53 follicle-stimulating hormone (FSH) values in non-diabetic postmenopausal women. These findings 54 suggest a potential mediating role of IR in FSH-induced BMD suppression in non-diabetic 55 postmenopausal women, leading to a deeper understanding of the mechanisms underlying the BMD 56 decline in postmenopausal women. Thus, it is important to explore strategies for regulating glucose 57 metabolism within an optimal range to promote metabolic and bone health in this population. 58 59Another study [5] investigated the correlation between KLF14 rs4731702 single nucleotide 60 polymorphism (SNP) and the risk of type 2 diabetes mellitus (T2DM) and dyslipidemia across various 61 ethnic groups. Three study groups -healthy subjects, patients with T2DM, and patients with 62 cardiometabolic disorders -underwent biochemical analysis for glycemic and lipid biomarkers, along 63 with genotyping for KLF14 rs4731702 SNP using the Tetra ARMS-PCR method. Results revealed that 64 KLF14 rs4731702 is associated with altered glycemic biomarkers and lipid profile in T2DM patients. 65 Specifically, individuals with the C allele exhibited higher IR and a worse lipid profile as compared to 66 the T allele carriers. This study also found that the prevalence of KLF14
  • Inhibition of Crif1 protects fatty acid-induced POMC neuron-like cell-line damage by increasing CPT-1 function
    Lara Regina-Ferreira, Fernando Valdivieso-Rivera, Monara K. S. C. Angelim, Larissa Menezes dos Reis, Vanessa O. Furino, Joseane Morari, Lizandra Maia de Sousa, Sílvio Roberto Consonni, Carlos H. Sponton, Pedro M. Moraes-Vieira, Lício A. Velloso
    American Journal of Physiology Endocrinology and Metabolism, 2024
    Saturated fats can damage hypothalamic neurons resulting in positive energy balance, and this is mitigated by mild cellular stress; however, the mechanisms behind this protective effect are unknown. Using a proopiomelanocortin cell line, we show that under exposure to a high concentration of palmitate, the partial inhibition of the mitochondrial protein Crif1 results in protection due to a metabolic shift warranted by the increased expression and activity of the mitochondrial fatty acid transporter CPT-1.
  • Investigation of Beige Fat Biology and Metabolism Using the CRISPR SunTag-p65-HSF1 Activation System
    Fernando Bladimir Valdivieso-Rivera, Vanessa de Oliveira Furino, Carlos Henrique Sponton
    Journal of Visualized Experiments, 2023
    Clustered regularly interspaced short palindromic repeats (CRISPR) technology has prompted a revolution in biology, and recent tools have been applied far beyond the originally described gene editing. The CRISPR activation (CRISPRa) system combines the catalytically inactive Cas9 (dCas9) protein with distinct transcription modules to induce endogenous gene expression. SunTag-p65-HSF1 (SPH) is a recently developed CRISPRa technology that combines components of synergistic activation mediators (SAMs) with the SunTag activators. This system allows the overexpression of single or multiple genes by designing a customized single-guide RNA (sgRNA). In this study, a previously developed SPH mouse was used to generate a conditional mouse expressing SPH in adipocytes (adiponectin Cre lineage), named AdipoSPH. To induce a white-to-beige fat (browning) phenotype, an adeno-associated virus (AAV) carrying sgRNA targeting the endogenous Prdm16 gene (a well-established transcription factor related to brown and beige fat development) was injected into the inguinal white adipose tissue (iWAT). This mouse model induced the expression of endogenous Prdm16 and activated the thermogenic gene program. Moreover, in vitro SPH-induced Prdm16 overexpression enhanced the oxygen consumption of beige adipocytes, phenocopying the results of a previous Prdm16 transgenic mouse model. Thus, this protocol describes a versatile, cost-effective, and time-effective mouse model for investigating adipose tissue biology.
  • What puts the heat on thermogenic fat: metabolism of fuel substrates
    Carlos H. Sponton, Jose Carlos de Lima-Junior, Luiz O. Leiria
    Trends in Endocrinology and Metabolism, 2022
  • The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT–liver communication
    Carlos H Sponton, Takashi Hosono, Junki Taura, Mark P Jedrychowski, Takeshi Yoneshiro, Qiang Wang, Makoto Takahashi, Yumi Matsui, Kenji Ikeda, Yasuo Oguri, Kazuki Tajima, Kosaku Shinoda, Rachana N Pradhan, Yong Chen, Zachary Brown, Lindsay S Roberts, Carl C Ward, Hiroki Taoka, Yoko Yokoyama, Mitsuhiro Watanabe, Hiroshi Karasawa, Daniel K Nomura, Shingo Kajimura
    EMBO Reports, 2020
  • Opposing action of NCoR1 and PGC-1α in mitochondrial redox homeostasis
    Tanes I. Lima, Dimitrius Santiago P.S.F. Guimarães, André G. Oliveira, Hygor Araujo, Carlos H.G. Sponton, Nadja C. Souza-Pinto, Ângela Saito, Ana Carolina M. Figueira, Soledad Palameta, Marcio Chaim Bajgelman, Andrea Calixto, Silas Pinto, Marcelo A. Mori, Joey Orofino, Valentina Perissi, Adrienne Mottis, Johan Auwerx, Leonardo Reis Silveira
    Free Radical Biology and Medicine, 2019
  • BCAA catabolism in brown fat controls energy homeostasis through SLC25A44
    Takeshi Yoneshiro, Qiang Wang, Kazuki Tajima, Mami Matsushita, Hiroko Maki, Kaori Igarashi, Zhipeng Dai, Phillip J. White, Robert W. McGarrah, Olga R. Ilkayeva, Yann Deleye, Yasuo Oguri, Mito Kuroda, Kenji Ikeda, Huixia Li, Ayano Ueno, Maki Ohishi, Takamasa Ishikawa, Kyeongkyu Kim, Yong Chen, Carlos Henrique Sponton, Rachana N. Pradhan, Homa Majd, Vanille Juliette Greiner, Momoko Yoneshiro, Zachary Brown, Maria Chondronikola, Haruya Takahashi, Tsuyoshi Goto, Teruo Kawada, Labros Sidossis, Francis C. Szoka, Michael T. McManus, Masayuki Saito, Tomoyoshi Soga, Shingo Kajimura
    Nature, 2019
  • Thermal stress induces glycolytic beige fat formation via a myogenic state
    Yong Chen, Kenji Ikeda, Takeshi Yoneshiro, Annarita Scaramozza, Kazuki Tajima, Qiang Wang, Kyeongkyu Kim, Kosaku Shinoda, Carlos Henrique Sponton, Zachary Brown, Andrew Brack, Shingo Kajimura
    Nature, 2019
  • Essential role of the PGC-1α/PPARβ axis in Ucp3 gene induction
    Tanes I. Lima, Dimitrius Guimarães, Carlos H. Sponton, Marcio C. Bajgelman, Soledad Palameta, Jessica M. Toscaro, Osvaldo Reis, Leonardo R. Silveira
    Journal of Physiology, 2019
  • AAV-mediated gene therapy as a strategy to fight obesity and metabolic diseases
    Carlos Henrique Sponton, Shingo Kajimura
    EMBO Molecular Medicine, 2018
  • Multifaceted roles of beige fat in energy homeostasis beyond UCP1
    Carlos Henrique Sponton, Shingo Kajimura
    Endocrinology, 2018
  • Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism
    Xiaodan Lu, Svetlana Altshuler-Keylin, Qiang Wang, Yong Chen, Carlos Henrique Sponton, Kenji Ikeda, Pema Maretich, Takeshi Yoneshiro, Shingo Kajimura
    Science Signaling, 2018
  • Evaluation of maximal lactate steady state in middle-aged hypertensive women
    Maycon Júnior Ferreira, Aline Pincerato Jarrete, Rodrigo Degli Esposti, Carlos Henrique Grossi Sponton, Chadi Pelegrini Anaruma, Angelina Zanesco
    Motriz Revista De Educacao Fisica, 2018
  • Burning Fat and Building Bone by FSH Blockade
    Carlos Henrique Sponton, Shingo Kajimura
    Cell Metabolism, 2017
  • Role of microRNAs on the Regulation of Mitochondrial Biogenesis and Insulin Signaling in Skeletal Muscle
    Tanes I. Lima, Hygor N. Araujo, Eveline S. Menezes, Carlos H. Sponton, Michel B. Araújo, Lucas H.M. Bomfim, André L. Queiroz, Madla A. Passos, Thais Amaral e Sousa, Sandro M. Hirabara, Amanda R. Martins, Helena C.L.B. Sampaio, Alice Rodrigues, Rui Curi, Everardo M. Carneiro, Antônio C. Boschero, Leonardo R. Silveira
    Journal of Cellular Physiology, 2017
  • Interleukin-6 increases the expression and activity of insulindegrading enzyme
    Mirian A. Kurauti, José M. Costa-Júnior, Sandra M. Ferreira, Gustavo J. Santos, Carlos H. G. Sponton, Everardo M. Carneiro, Guilherme D. Telles, Mara P. T. Chacon-Mikahil, Cláudia R. Cavaglieri, Luiz F. Rezende, Antonio C. Boschero
    Scientific Reports, 2017
  • Heart rate variability and plasma biomarkers in patients with type 1 diabetes mellitus: Effect of a bout of aerobic exercise
    Chadi P. Anaruma, Maycon Ferreira, Carlos H.G. Sponton, Maria A. Delbin, Angelina Zanesco
    Diabetes Research and Clinical Practice, 2016
  • The presence of the NOS3 gene polymorphism for intron 4 mitigates the beneficial effects of exercise training on ambulatory blood pressure monitoring in adults
    Carlos H. Sponton, Rodrigo Esposti, Cynara M. Rodovalho, Maycon J. Ferreira, Aline P. Jarrete, Chadi P. Anaruma, Mauricio Bacci, Angelina Zanesco
    American Journal of Physiology Heart and Circulatory Physiology, 2014
  • Prevalence of dyslipidemia in middle-aged adults with NOS3 gene polymorphism and low cardiorespiratory fitness
    Pamella A. Malagrino, Carlos H. G. Sponton, Rodrigo D. Esposti, Carla F. Franco-Penteado, Romulo A. Fernandes, Marcos André C. Bezerra, Dulcinéia M. Albuquerque, Cynara M. Rodovalho, Maurício Bacci, Angelina Zanesco
    Arquivos Brasileiros De Endocrinologia E Metabologia, 2013
  • Effect of exercise training on the cardiovascular and biochemical parameters in women with eNOS gene polymorphism
    Tiago M. Rezende, Carlos H.G. Sponton, Pamella A. Malagrino, Marcos A.C. Bezerra, Carla F.F. Penteado, Angelina Zanesco
    Archives of Physiology and Biochemistry, 2011
  • Influence of eNOS gene polymorphism on cardiometabolic parameters in response to physical training in postmenopausal women
    R.D. Esposti, C.H.G. Sponton, P.A. Malagrino, F.C. Carvalho, E. Peres, G.M. Puga, I.P. Novais, D.M. Albuquerque, C. Rodovalho, M. Bacci, A. Zanesco
    Brazilian Journal of Medical and Biological Research, 2011
  • Effects of physical exercise and cinnamon extract on blood chemistry of type 1 diabetic rats
    Journal of Exercise Physiology Online, 2010
  • Women with TT genotype for eNOS gene are more responsive in lowering blood pressure in response to exercise
    Carlos H.G. Sponton, Tiago M. Rezende, Pamella A. Mallagrino, Carla F. Franco-Penteado, Marcos André C. Bezerra, Angelina Zanesco
    European Journal of Preventive Cardiology, 2010