About

Shingo Kajimura, PhD, is a professor based at the Division of Endocrinology, Diabetes & Metabolism at Beth Israel Deaconess Medical Center and the Department of Medicine at Harvard Medical School. He is also affiliated with the Howard Hughes Medical Institute (HHMI) and is a member of the Metabolism Program at the Broad Institute. His laboratory focuses on understanding the molecular basis of bioenergetics in health and disease, specifically how the body controls energy balance and how these processes malfunction in conditions such as obesity, diabetes, cancer, and aging. The overarching goal of his research is to develop a blueprint for rewiring bioenergetic circuitry through defined factors to improve metabolic health. A particular emphasis of his lab is on adipose tissue, which dynamically remodels its cellular composition, metabolism, and function in response to various external and internal cues including nutrition, hormonal signals, and temperature. This metabolic adaptation involves processes such as differentiation, mitochondrial biogenesis and clearance, lipolysis and lipogenesis, and thermogenesis, all of which play a central role in regulating whole-body energy homeostasis. Defects in these processes can lead to obesity, insulin resistance, dyslipidemia, cardiovascular diseases, and certain types of cancer. The Kajimura Lab is composed of a multidisciplinary and international team of molecular biologists, biochemists, physiologists, and clinicians working collaboratively. The laboratory receives support from HHMI, the National Institutes of Health (NIH), Pew Charitable Trust, and other private foundations.

Research topics

• Biology
• Cell biology
• Endocrinology
• Genetics
• Computer Science
• Computational biology
• Gerontology
• Library science
• Medicine
• Biochemistry
• Immunology

Selected publications

• N-Palmitoyl Glutamine Is a Candidate Mediator of Cardiorespiratory Fitness

  Circulation · 2025-11-12 · 5 citations

  articleOpen access

  BACKGROUND: Cardiorespiratory fitness is an integrative measure of cardiometabolic health and predictor of survival, yet little is known about its molecular underpinnings. Small molecule metabolites and lipids are increasingly recognized as exercise-stimulated signaling molecules and candidate molecular transducers of cardiorespiratory fitness. METHODS: We performed nontargeted liquid chromatography mass spectrometry–based plasma metabolomics in 654 participants (mean age, 35 years; 55% women) from the HERITAGE Family Study (Health, Risk Factors, Exercise Training, and Genetics) who had cardiorespiratory fitness (maximal oxygen uptake [VO 2 max]) measured by cardiopulmonary exercise testing and underwent 20 weeks of supervised endurance training. Metabolite–VO 2 max relationships were assessed using linear regression and tested for replication in FHS (Framingham Heart Study) participants who also underwent cardiopulmonary exercise testing. Metabolite relationships with incident all-cause mortality ascertained in JHS (Jackson Heart Study) and MESA (Multi-Ethnic Study of Atherosclerosis) were tested using Cox regression. Experimental studies of cellular respiration and mitochondrial function were performed in C2C12 myotubes. RESULTS: An unknown mass spectrometry peak (mass-to-charge, 385.3056; retention time, 3.69 minutes) had the strongest, positive relationship with VO 2 max (mL×kg −1 min −1 ) after adjustment for age, sex, race, and lean body mass (β=1.29; false discovery rate q =5.3×10 −6 ); was identified as N-palmitoyl glutamine (N-pal-gln) using tandem mass spectrometry and bioinformatics; and was confirmed with an authentic chemical standard. The biological role of N-pal-gln has not been described previously. The relationship of N-pal-gln with VO 2 max was validated in 408 participants from the FHS (β=1.2; P =3.8×10 −5 ), and its levels increased after exercise training (log fold change=0.22; q =5.3×10 −12 ). N-pal-gln levels were inversely associated with all-cause mortality in JHS and MESA (hazard ratio, 0.91 and 0.65 [ P =0.029 and P =0.028], respectively). Previous studies have shown that structurally related biochemicals modulate energy homeostasis; thus, we performed mitochondrial experiments. N-pal-gln administration led to a dose-dependent increase in mitochondrial:nuclear DNA ratio compared with control treated cells (15% and 20% increases at 6.5 nM and 26 nM N-pal-gln, respectively [ P =0.04 and P =0.02]) and improved bioenergetics (N-pal-gln at 26 nM increased the phosphate:oxygen ratio across ADP concentrations from 0 to 100 μM; ANOVA P =0.0027). CONCLUSIONS: We identified a novel, lipidated amino acid, N-pal-gln, that is positively associated with VO 2 max, increases after regular aerobic exercise, and is inversely associated with incident mortality. N-pal-gln stimulates mitochondrial biogenesis and efficiency, demonstrating its potential role as an exercise-stimulated transducer of cardiorespiratory fitness.

  PublisherOA PDFDOI

• Mitochondrial control of fuel switching via carnitine biosynthesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-18

  articleOpen accessSenior authorCorresponding

  Metabolic adaptation to environmental changes, such as fasting and cold exposure, involves a dynamic shift in fuel utilization from glucose to fatty acid oxidation, a process that relies on carnitine-mediated fatty acid oxidation in mitochondria. While dietary sources of animal origin (e.g., red meat) contribute to the carnitine pool, de novo carnitine synthesis from trimethyllysine (TML) is essential, particularly for those whose dietary sources are vegetables and fruits that contain negligible amounts of carnitine. However, the molecular pathway of de novo carnitine synthesis and its physiological significance remain poorly understood. Here, we showed that SLC25A45 is a mitochondrial TML carrier that controls de novo carnitine biosynthesis in vivo. Genetic loss of SLC25A45 results in systemic carnitine and acylcarnitine deficiency, leading to impaired fatty acid oxidation and thermogenesis during cold adaptation, while promoting glucose catabolism. Notably, Slc25a45-deficient mice maintained a high respiratory exchange ratio and impaired lipid mobilization following treatment with a GLP1 receptor agonist (GLP-1RA), rendering them resistant to GLP-1RA-induced adipose tissue loss. Together, the present study identifies SLC25A45 as a regulatory checkpoint in fuel switching during adaptation, with implications for systemic energy balance and response to GLP-1RA-mediated anti-obesity therapy.

  PublisherDOI

• Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue

  Cell Metabolism · 2025-04-08 · 18 citations

  articleOpen accessSenior author

  import that plays a key role in UCP1-independent thermogenesis and energy balance.

  PublisherDOI

• BAT-Derived Metabolome Atlas Identifies Circulating Mediators of Hepatic Oxidative Stress

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access1st authorCorresponding
  PublisherDOI

• A new UCP1-independent thermogenic mechanism in peroxisomes

  Molecular Cell · 2025-11-01

  articleSenior author
  PublisherDOI

• Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration

  Nature Metabolism · 2025-11-20

  articleOpen access

  Abstract Nicotinamide adenine dinucleotide (NAD + ) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD + in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD + in hepatocyte mitochondria. We find that the mitochondrial NAD + concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD + content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD + precursor supplements. This benefit is observed even though NAD + levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD + pool is a key determinant of the rate of liver regeneration.

  PublisherOA PDFDOI

• Glycerolipid Cycling in Thermogenesis, Energy Homeostasis, Signaling, and Diseases

  Physiological Reviews · 2025-06-09 · 15 citations

  reviewOpen access

  Mammals maintain body heat by adaptive energy expenditure through different organ-specific mechanisms. The glycerolipid/free fatty acid (FFA) cycle (glycerolipid cycle), encompassing triglyceride lipolysis and FFA release followed by their reesterification, is an ATP-consuming process that contributes to energy expenditure, heat production, and various lipid signaling pathways. The glycerolipid cycle, which was originally described as a whole body process, is now known to also occur intracellularly in many organs. This review focuses on the thermogenic and signaling roles of glycerolipid cycling in adipose and other tissues and offers insight into the various pathophysiological conditions where its activity is altered. We discuss its substrates and products, enzyme components, and regulation. We present evidence that this cycling process, besides acting as the complete triglyceride/FFA cycle, is in fact composed of multiple shorter subcycles, which can be activated individually. We highlight the importance of this energy-dissipating cycle in adaptive thermogenesis and energy expenditure in animals and humans and discuss the latest methodological advances to quantify its flux. The much renewed interest in this area has begun to showcase the central role of glycerolipid cycling mediated thermogenesis and signaling in cardiometabolic diseases, cancer, and aging that could be harnessed for therapy.

  PublisherDOI

• Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis

  Nature Communications · 2025-08-20 · 5 citations

  articleOpen access

  A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.

  PublisherOA PDFDOI

• Mitochondrial control of glycerolipid synthesis by a PEP shuttle

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-16

  articleOpen accessSenior author

  Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.

  PublisherDOI

• An Unexpected Journey Into Brown Fat Research for Metabolic Health: The 2025 Outstanding Scientific Achievement Award Lecture

  Diabetes · 2025-11-20 · 1 citations

  article1st authorCorresponding

  For many years, brown adipose tissue (BAT) was primarily regarded as a "heat organ" for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT in metabolic health, including systemic glucose homeostasis, lipid metabolism, insulin sensitivity, and protection against cardiometabolic disease. In this award lecture, I highlight key contributions from our laboratory and others that transformed brown fat research, including molecular insights into brown and beige adipocyte biogenesis and the discovery of UCP1-independent pathways through which brown and beige fat influence metabolic health beyond thermogenesis.

  PublisherDOI

Recent grants

• Biological roles and developmental pathway of burn-induced beige fat in humans

  NIH · $630k · 2016–2019

• Molecular mechanisms of UCP1-independent pathways in metabolic health

  NIH · $5.2M · 2012–2029

• NIH Grant R00DK087853

  NIH · $634k · 2015

• Post-translational control of adipose tissue remodeling and metabolic health

  NIH · $2.6M · 2020–2026

• Mitochondrial BCAA transporter in physiology and disease

  NIH · $1.8M · 2020–2025

Frequent coauthors

• Bruce M. Spiegelman

  Dana-Farber Cancer Institute

  65 shared

• Kosaku Shinoda

  Albert Einstein College of Medicine

  59 shared

• Kenji Ikeda

  Osaka University

  55 shared

• Takeshi Yoneshiro

  The University of Tokyo

  54 shared

• Ichitaro Abe

  Beth Israel Deaconess Medical Center

  38 shared

• Christopher Auger

  Howard Hughes Medical Institute

  36 shared

• Kazuki Tajima

  33 shared

• Pere Puigserver

  Dana-Farber Cancer Institute

  33 shared

Awards & honors

• Howard Hughes Medical Institute (HHMI), Associate Member at…