Mapping of biguanide transporters in human fat cells and their impact on lipolysis

Arner, Peter; Kulyté, Agné; Batchelor, Kenneth W.; Laurencikiene, Jurga; Livingston, James N.

doi:10.1111/dom.13395

Cited by 15 publications

(9 citation statements)

References 32 publications

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“…The activation of AMPK reduces cell proliferation through negatively regulates mTOR signaling (43). Recent results showed that NT-1044 exhibited higher AMPK activation than metformin at the same dosage in differentiated human adipocytes (44).In its role as an AMPK activator, the anti-tumorigenic activity of NT-1044 appears similar to that of metformin, which has been shown to significantly decrease proliferation of several human cancer cell lines in vitro, including endometrial cancer (25,26,(45)(46)(47). Since AMPK negatively controls mTOR activation and mTOR is a downstream effector of AKT, Activation of AMPK is considered to be a possible therapeutic target for cancers that contain high AKT activity (48).…”

Section: Discussionmentioning

confidence: 99%

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

et al. 2021

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ObjectivesAnti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model.MethodsCell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks.ResultsNT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 μM for Ishikawa; 87 μM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice.ConclusionsNT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

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Section: Discussionmentioning

confidence: 99%

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

et al. 2021

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“…Assessment of isoprenaline-stimulated lipolysis in si NUP85 -transfected hASCs was performed as described previously 19 . In brief, cells were incubated for 3 h in DMEM/F12 medium supplemented with 20 mg/ml of BSA and with or without isoprenaline (1 µmol/l).…”

Section: Methodsmentioning

confidence: 99%

Shared genetic loci for body fat storage and adipocyte lipolysis in humans

Kulyté

Lundbäck

Arner

et al. 2022

Sci Rep

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Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.

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“…This figure is a graphical representation of the data assimilated by Prof. Hermann Koepsell in Table 6 of his 2020 review, Organic Cation Transporters in Health and Disease 9 for OCT1, OCT2, OCT3, MATE1, and MATE2-K, based on >130 references therein; plus data reported for PMAT expression by numerous research labs. 5,[10][11][12][13][14] The vast majority of these distribution data is based upon mRNA expression reports, not protein expression. Tissues reported include adipose tissue, adrenal glands, bladder, bone marrow, brain and neurovasculature, eye, heart, intestines, kidney, liver, lungs/trachea, salivary glands, skeletal muscle, skin, spleen, stomach, thymus and thyroid.…”

Section: Pharmacological Findingsmentioning

confidence: 99%

“… Distribution of uptake 2 transporters in major organs and tissues throughout the body . This figure is a graphical representation of the data assimilated by Prof. Hermann Koepsell in Table 6 of his 2020 review, Organic Cation Transporters in Health and Disease 9 for OCT1, OCT2, OCT3, MATE1, and MATE2‐K, based on >130 references therein; plus data reported for PMAT expression by numerous research labs 5,10–14 . The vast majority of these distribution data is based upon mRNA expression reports, not protein expression.…”

Section: Introductionmentioning

confidence: 99%

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

Weber

Beaver

Gilman

2022

Basic Clin Pharma Tox

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Burgeoning literature demonstrates that monoamine transporters with high transport capacity but lower substrate affinity (i.e., uptake 2) contribute meaningfully to regulation of monoamine neurotransmitter signalling. However, studying behavioural influences of uptake 2 is hindered by an absence of selective inhibitors largely free of off‐target, confounding effects. This contrasts with study of monoamine transporters with low transport capacity but high substrate affinity (i.e., uptake 1), for which there are many reasonably selective inhibitors. To circumvent this dearth of pharmacological tools for studying uptake 2, researchers have instead employed mice with constitutive genetic deficiency in three separate transporters. By studying baseline behavioural shifts, plus behavioural responses to environmental and pharmacological manipulations—the latter primarily targeting uptake 1—investigators have been creatively characterizing the behavioural, and often sex‐specific, influences of uptake 2. This non‐systematic mini review summarizes current uptake 2 behaviour literature, highlighting emphases on stress responsivity in organic cation transporter 2 (OCT2) work, psychostimulant responsivity in OCT3 and plasma membrane monoamine transporter (PMAT) investigations, and antidepressant responsivity in all three. Collectively, this small but growing body of work reiterates the necessity for development of selective uptake 2‐inhibiting drugs, with reviewed studies suggesting that these might advance personalized treatment approaches.

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Mapping of biguanide transporters in human fat cells and their impact on lipolysis

Abstract: While human fat cells primarily express three biguanide transporters, our data suggest that PMAT is the primary target for development of fat cell-specific antilipolytic biguanides with high sensitivity and potency.

Cited by 15 publications

References 32 publications

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

Shared genetic loci for body fat storage and adipocyte lipolysis in humans

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters

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