Publications by authors named "Rudolph L Leibel"

143 Publications

The postnatal leptin surge in mice is variable in both time and intensity and reflects nutritional status.

Int J Obes (Lond) 2021 Sep 2. Epub 2021 Sep 2.

Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Background/objectives: The murine postnatal leptin surge occurs within the first 4 weeks of life and is critical for neuronal projection development within hypothalamic feeding circuits. Here we describe the influence of nutritional status on the timing and magnitude of the postnatal leptin surge in mice.

Methods: Plasma leptin concentrations were measured 1-3 times per week for the first 4 weeks of life in C57BL/6J pups reared in litters adjusted to 3 (small), 7-8 (normal), or 11-12 (large) pups per dam fed breeder chow or raised in litters of 7-8 by dams fed high-fat diet (HFD) ad libitum starting either prior to conception or at parturition.

Results: Mice raised in small litters become fatter than pups raised in either normal or large litters. The leptin surge in small litter pups starts earlier, lasts longer, and is dramatically larger in magnitude compared to normal litter pups, even when leptin concentrations are normalized to fat mass. In mice reared in large litters, weight gain is diminished and the surge is both significantly delayed and lower in magnitude compared to control pups. Pups reared by HFD-fed dams (starting preconception or at parturition) are fatter and have augmented leptin surge magnitude compared to pups suckled by chow-fed dams. Surge timing varies depending upon nutritional status of the pup; the source of the surge is primarily subcutaneous adipose tissue. At peak leptin surge, within each group, fat mass and plasma leptin are uncorrelated; in comparison with adults, pups overproduce leptin relative to fat mass. Plasma leptin elevation persists longer than previously described; at postnatal day 27 mice continue overproducing leptin relative to fat mass.

Conclusions: In mice, small litter size and maternal HFD feeding during the perinatal period augment the plasma leptin surge whereas large litter size is associated with a delayed surge of reduced magnitude.
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http://dx.doi.org/10.1038/s41366-021-00957-5DOI Listing
September 2021

Gene expression atlas of energy balance brain regions.

JCI Insight 2021 Aug 23;6(16). Epub 2021 Aug 23.

Naomi Berrie Diabetes Center, College of Physicians and Surgeons.

Energy balance is controlled by interconnected brain regions in the hypothalamus, brainstem, cortex, and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryo punch biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare, and low-frequency coding variants; GWAS; syndromic) was analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct "modules" of similar expression profile, and these were distinct from expression modules formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance-relevant brain regions.
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http://dx.doi.org/10.1172/jci.insight.149137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409984PMC
August 2021

Word selection and weight bias.

Obesity (Silver Spring) 2021 Aug 14;29(8):1238. Epub 2021 Jun 14.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

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http://dx.doi.org/10.1002/oby.23203DOI Listing
August 2021

SNORD116 and growth hormone therapy impact IGFBP7 in Prader-Willi syndrome.

Genet Med 2021 May 26. Epub 2021 May 26.

Centre de Physiopathologie de Toulouse Purpan, CPTP, UMR INSERM 1043 CNRS 5828, Université Paul Sabatier, Toulouse, France.

Purpose: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS.

Methods: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness.

Results: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1.

Conclusion: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.
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http://dx.doi.org/10.1038/s41436-021-01185-yDOI Listing
May 2021

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

J Pediatr Endocrinol Metab 2021 May 13;34(5):633-638. Epub 2021 Apr 13.

Department of Pediatrics, Division of Molecular Genetics, Columbia University Medical Center, New York, NY, USA.

Objectives: There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY.

Methods: We used a tiered testing approach focusing initially on and and then expanding to exome sequencing for those individuals without identified mutations in or . The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%.

Results: Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in or . Less frequently, mutations were identified in , , , and . For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation.

Conclusions: Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.
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http://dx.doi.org/10.1515/jpem-2020-0501DOI Listing
May 2021

Describing the Weight-Reduced State: Physiology, Behavior, and Interventions.

Obesity (Silver Spring) 2021 04;29 Suppl 1:S9-S24

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

Although many persons with obesity can lose weight by lifestyle (diet and physical activity) therapy, successful long-term weight loss is difficult to achieve, and most people who lose weight regain their lost weight over time. The neurohormonal, physiological, and behavioral factors that promote weight recidivism are unclear and complex. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop in June 2019, titled "The Physiology of the Weight-Reduced State," to explore the mechanisms and integrative physiology of adaptations in appetite, energy expenditure, and thermogenesis that occur in the weight-reduced state and that may oppose weight-loss maintenance. The proceedings from the first session of this workshop are presented here. Drs. Michael Rosenbaum, Kevin Hall, and Rudolph Leibel discussed the physiological factors that contribute to weight regain; Dr. Michael Lowe discussed the biobehavioral issues involved in weight-loss maintenance; Dr. John Jakicic discussed the influence of physical activity on long-term weight-loss maintenance; and Dr. Louis Aronne discussed the ability of drug therapy to maintain weight loss.
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http://dx.doi.org/10.1002/oby.23086DOI Listing
April 2021

Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons.

J Clin Invest 2021 04;131(8)

Naomi Berrie Diabetes Center and.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.
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http://dx.doi.org/10.1172/JCI146287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262481PMC
April 2021

FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice.

Mol Metab 2021 Jul 10;49:101187. Epub 2021 Feb 10.

Forkhead BioTherapeutics, Inc., New York, NY, USA. Electronic address:

Objective: Forkhead box protein O1 (FOXO1) plays a key role in regulating hepatic glucose production, but investigations of FOXO1 inhibition as a potential therapeutic approach have been hampered by a lack of selective chemical inhibitors. By profiling structurally diverse FOXO1 inhibitors, the current study validates FOXO1 as a viable target for the treatment of diabetes.

Methods: Using reporter gene assays, hepatocyte gene expression studies, and in vivo studies in mice, we profiled our leading tool compound 10 and a previously characterized FOXO1 inhibitor, AS1842856 (AS).

Results: We show that AS has significant FOXO1-independent effects, as demonstrated by testing in FOXO1-deficient cell lines and animals, while compound 10 is highly selective for FOXO1 both in vitro and in vivo and fails to elicit any effect in genetic models of FOXO1 ablation. Chronic administration of compound 10 improved insulin sensitivity and glucose control in db/db mice without causing weight gain. Furthermore, chronic compound 10 treatment combined with FGF21 led to synergistic glucose lowering in lean, streptozotocin-induced diabetic mice.

Conclusions: We show that the widely used AS compound has substantial off-target activities and that compound 10 is a superior tool molecule for the investigation of FOXO1 function. In addition, we provide preclinical evidence that selective FOXO1 inhibition has potential therapeutic benefits for diabetes as a monotherapy or in combination with FGF21.
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http://dx.doi.org/10.1016/j.molmet.2021.101187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966865PMC
July 2021

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci.

Elife 2021 Jan 18;10. Epub 2021 Jan 18.

Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States.

To uncover novel significant association signals (p<5×10), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 × 10≤p<5×10) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5×10 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at , , and . Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.
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http://dx.doi.org/10.7554/eLife.62206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815306PMC
January 2021

Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease.

Cell Mol Gastroenterol Hepatol 2021 16;11(3):667-682. Epub 2020 Oct 16.

Center for Spatial and Functional Genomics, Philadelphia, Pennsylvania; Division of Human Genetics, Philadelphia, Pennsylvania; Division of Diabetes and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background & Aims: Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD.

Methods: We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways.

Results: We found significant genetic correlations (rg) of 0.122 with an adjusted P (P) = 1.4 × 10 for IBD: rg = 0.122; P = 2.5 × 10 for ulcerative colitis and genetic correlation (rg) = 0.094; P = 2.5 × 10 for Crohn's disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms.

Conclusions: Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.
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http://dx.doi.org/10.1016/j.jcmgh.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843407PMC
October 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.
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http://dx.doi.org/10.1172/jci.insight.138576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526459PMC
September 2020

Differences in brain structure and function in children with the obesity-risk allele.

Obes Sci Pract 2020 Aug 1;6(4):409-424. Epub 2020 Apr 1.

Department of Psychiatry Columbia University Irving Medical Center New York New York USA.

Objective: Noncoding alleles of the fat mass and obesity-associated () gene have been associated with obesity risk, yet the underlying mechanisms remain unknown. Risk allele carriers show alterations in brain structure and function, but previous studies have not disassociated the effects of genotype from those of body mass index (BMI).

Methods: Differences in brain structure and function were examined in children without obesity grouped by their number of copies (0,1,2) of the FTO obesity-risk single-nucleotide polymorphism (SNP) rs1421085. One hundred five 5- to 10-year-olds (5th-95th percentile body fat) were eligible to participate. Usable scans were obtained from 93 participants (15 CC [homozygous risk], 31 CT [heterozygous] and 47 TT [homozygous low risk]).

Results: Homozygous C allele carriers (CCs) showed greater grey matter volume in the cerebellum and temporal fusiform gyrus. CCs also demonstrated increased bilateral cerebellar white matter fibre density and increased resting-state functional connectivity between the bilateral cerebellum and regions in the frontotemporal cortices.

Conclusions: This is the first study to examine brain structure and function related to alleles in young children not yet manifesting obesity. This study lends support to the notion that the cerebellum may be involved in -related risk for obesity, yet replication and further longitudinal study are required.
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http://dx.doi.org/10.1002/osp4.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448161PMC
August 2020

Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells.

Cell 2020 06 20;181(6):1263-1275.e16. Epub 2020 May 20.

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.
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http://dx.doi.org/10.1016/j.cell.2020.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293577PMC
June 2020

Retinol-binding protein 2 (RBP2) binds monoacylglycerols and modulates gut endocrine signaling and body weight.

Sci Adv 2020 03 11;6(11):eaay8937. Epub 2020 Mar 11.

Department of Medicine, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. -deficient ( ) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.
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http://dx.doi.org/10.1126/sciadv.aay8937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065888PMC
March 2020

Physiological consequences of transient hyperleptinemia during discrete developmental periods on body weight in mice.

Sci Transl Med 2020 01;12(524)

Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.

Leptin plays a role in central nervous system developmental programs and intercurrent physiological processes related to body fat regulation. The timing and neuromolecular mechanisms for these effects are relevant to the prevention and treatment of obesity. Factors implicated in a body weight "set point" including dietary fat, circulating leptin, and other adipokines tend to covary with adiposity and are difficult to disarticulate experimentally. To dissociate leptin effects from adiposity and diet, we created a transgenic mouse in which leptin expression is regulated by doxycycline exposure. Using this system, we investigated the physiological consequences of developmentally-timed transient hyperleptinemia on subsequent adiposity. We evaluated physiological effects of leptin elevation during adulthood (9 to 29 weeks old), "adolescence" (3 to 8 weeks old), and the immediate postnatal period [postnatal days 0 to 22 (P0 to P22)] on long-term adiposity and susceptibility to gain weight on high-fat diet (HFD) fed ad libitum. We found that inducing chronic hyperleptinemia in adult or "adolescent" mice did not alter body weight when excess leptin was discontinued, and upon later exposure to HFD, weight gain did not differ from controls. However, transient elevation of circulating leptin from P0 to P22 increased weight and fat gain in response to HFD, indicating greater susceptibility to obesity as adults. Thus, transient plasma leptin elevations-mimicking one aspect of transient adiposity-increased later susceptibility to diet-induced obesity, although these effects were restricted to a critical developmental (P0 to P22) time window. These findings may have clinical implications for weight management in infancy.
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http://dx.doi.org/10.1126/scitranslmed.aax6629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427106PMC
January 2020

Reply to DS Ludwig et al.

Am J Clin Nutr 2019 11;110(5):1255-1256

Pennington Biomedical Research Center, Orlando, FL.

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http://dx.doi.org/10.1093/ajcn/nqz157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307317PMC
November 2019

Auto-Regulation of Leptin Neurobiology.

Cell Metab 2019 10;30(4):614-616

Division of Molecular Genetics (Pediatrics) and the Naomi Berrie Diabetes Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. Electronic address:

The clinical use of the hormone leptin, a key regulator of food intake, to treat the most common instances of obesity has so far failed. In this issue, Zhao et al. (2019) report that, paradoxically, reducing leptin levels in obese mice increases their sensitivity to the concentrations that remain, and leads to reductions in weight gain, thus suggesting why these earlier trials may have failed and possibly a new approach to treating obesity.
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http://dx.doi.org/10.1016/j.cmet.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413296PMC
October 2019

Functional genomic characterization of the locus in African Americans.

Physiol Genomics 2019 11 18;51(11):517-528. Epub 2019 Sep 18.

Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.

Background: SNPs in the first intron of the fat mass and obesity-associated () gene represent the strongest genome-wide associations with adiposity [body mass index (BMI)]; the molecular basis for these associations is under intense investigation. In European populations, the focus of most genome-wide association studies conducted to date, the single nucleotide polymorphisms (SNPs) have indistinguishable associations due to the high level of linkage disequilibrium (LD). However, in African American (AA) individuals, reduced LD and increased haplotype diversity permit finer distinctions among obesity-associated SNPs. Such distinctions are important to mechanistic inferences and for selection of disease SNPs relevant to specific populations.

Methods: To identify specific SNP(s) directly related to adiposity, we performed: ) haplotype analyses of individual-level data in 3,335 AAs from the Atherosclerosis Risk in Communities Cohort (ARIC) study; as well as ) statistical fine-mapping using summary statistics from a study of in over 20 000 AAs and over 1000 functional genomic annotations.

Results: Our haplotype analyses suggest that in AAs at least two distinct signals underlie the intron 1 -adiposity signal. Fine mapping showed that two SNPs have the highest posterior probability of association (PPA) with BMI: rs9927317 (PPA = 0.94) and rs62033405 (PPA = 0.99). These variants overlap possible enhancer sites and the 5'-regions of transcribed genes in the substantia nigra, chondrocytes, and white adipocytes.

Conclusions: We found two SNPs in with the highest probability of direct association with BMI in AAs, as well as tissue-specific mechanisms by which these variants may contribute to the pathogenesis of obesity.
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http://dx.doi.org/10.1152/physiolgenomics.00057.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879815PMC
November 2019

The FTO Gene and Measured Food Intake in 5- to 10-Year-Old Children Without Obesity.

Obesity (Silver Spring) 2019 06;27(6):1023-1029

Division of Molecular Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.

Objective: Genetic variation in the first intron of FTO (e.g., single-nucleotide polymorphism [SNP] rs9939609) is strongly associated with adiposity. This effect is thought to be mediated (at least in part) via increasing caloric intake, although the precise molecular genetic mechanisms are not fully understood. Prior pediatric studies of FTO have included youth with overweight and obesity; however, they have not informed whether a genotypic effect on ingestive behavior is present prior to obesity onset. Therefore, this study investigated the association between FTO and caloric intake in children aged 5 to 10 years without obesity (adiposity ≤ 95th percentile).

Methods: A total of 122 children were genotyped for rs9939609 and ate ad libitum from a laboratory lunch buffet following a standardized breakfast. Linear regressions, adjusting for body mass, were used to examine the association between FTO "dose" (number of copies of SNP rs9939609) and intake variables.

Results: There was a significant association between FTO and total intake. Each risk allele predicted an additional 64 calories, accounting for 3% of the variance. There were no associations between FTO and macronutrient preference, energy density, or diet variety. Results were influenced by race.

Conclusions: Results corroborate and extend prior work by showing a dose-dependent effect on food intake in children without obesity.
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http://dx.doi.org/10.1002/oby.22464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561098PMC
June 2019

Glucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet.

Obesity (Silver Spring) 2019 06 8;27(6):971-981. Epub 2019 May 8.

Departments of Pediatrics and Medicine, Division of Molecular Genetics, Columbia University Irving Medical Center, New York, New York, USA.

Objective: The objective of this study was to measure changes in glucose, lipid, and inflammation parameters after transitioning from a baseline diet (BD) to an isocaloric ketogenic diet (KD).

Methods: Glucose homeostasis, lipid homeostasis, and inflammation were studied in 17 men (BMI: 25-35 kg/m ) during 4 weeks of a BD (15% protein, 50% carbohydrate, 35% fat) followed by 4 weeks of an isocaloric KD (15% protein, 5% carbohydrate, 80% fat). Postprandial responses were assessed following mixed-meal tests matched to compositions of the BD (control meal [CM]) and KD (ketogenic meal).

Results: Fasting ketones, glycerol, free fatty acids, glucagon, adiponectin, gastric inhibitory peptide, total and low-density lipoprotein cholesterol, and C-reactive protein were significantly increased on the KD. Fasting insulin, C-peptides, triglycerides, and fibroblast growth factor 21 were significantly decreased. During the KD, the glucose area under the curve was significantly higher with both test meals, and the insulin area under the curve was significantly higher only for the CM. Analyses of glucose homeostasis suggested that the KD insulin sensitivity decreased during the CM but increased during the ketogenic meal. Insulin-mediated antilipolysis was decreased on the KD regardless of meal type.

Conclusions: Switching to the KD was associated with increased cholesterol and inflammatory markers, decreased triglycerides, and decreased insulin-mediated antilipolysis. Glucose homeostasis parameters were diet dependent and test meal dependent.
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http://dx.doi.org/10.1002/oby.22468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922028PMC
June 2019

Methodologic considerations for measuring energy expenditure differences between diets varying in carbohydrate using the doubly labeled water method.

Am J Clin Nutr 2019 05;109(5):1328-1334

Pennington Biomedical Research Center, Baton Rouge, LA.

Background: Low-carbohydrate diets have been reported to significantly increase human energy expenditure when measured using doubly labeled water (DLW) but not by respiratory chambers. Although DLW may reveal true physiological differences undetected by respiratory chambers, an alternative possibility is that the expenditure differences resulted from failure to correctly estimate the respiratory quotient (RQ) used in the DLW calculations.

Objective: To examine energy expenditure differences between isocaloric diets varying widely in carbohydrate and to quantitatively compare DLW data with respiratory chamber and body composition measurements within an energy balance framework.

Design: DLW measurements were obtained during the final 2 wk of month-long baseline (BD; 50% carbohydrate, 35% fat, 15% protein) and isocaloric ketogenic diets (KD; 5% carbohydrate, 80% fat, 15% protein) in 17 men with a BMI of 25-35 kg/m2. Subjects resided 2 d/wk in respiratory chambers to measure energy expenditure (EEchamber). DLW expenditure was calculated using chamber-determined RQ either unadjusted (EEDLW) or adjusted (EEDLWΔRQ) for net energy imbalance using diet-specific coefficients. Accelerometers measured physical activity. Body composition changes were measured by dual-energy X-ray absorptiometry (DXA) which were combined with energy intake measurements to calculate energy expenditure by balance (EEbal).

Results: After transitioning from BD to KD, neither EEchamber nor EEbal were significantly changed (∆EEchamber = 24 ± 30 kcal/d; P = 0.43 and ∆EEbal = -141 ± 118 kcal/d; P = 0.25). Similarly, physical activity (-5.1 ± 4.8%; P = 0.3) and exercise efficiency (-1.6 ± 2.4%; P = 0.52) were not significantly changed. However, EEDLW was 209 ± 83 kcal/d higher during the KD (P = 0.023) but was not significantly increased when adjusted for energy balance (EEDLWΔRQ = 139 ± 89 kcal/d; P = 0.14). After removing 2 outliers whose EEDLW were incompatible with other data, EEDLW was marginally increased during the KD by 126 ± 62 kcal/d (P = 0.063) and EEDLW∆RQ was only 46 ± 65 kcal/d higher (P = 0.49).

Conclusions: DLW calculations failing to account for diet-specific energy imbalance effects on RQ erroneously suggest that low-carbohydrate diets substantially increase energy expenditure. This trial was registered at clinicaltrials.gov as NCT01967563.
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http://dx.doi.org/10.1093/ajcn/nqy390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499509PMC
May 2019

Transgenic substitution with Greater Amberjack Seriola dumerili fish insulin 2 in NOD mice reduces beta cell immunogenicity.

Sci Rep 2019 03 21;9(1):4965. Epub 2019 Mar 21.

Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.

Type I diabetes (T1D) is caused by immune-mediated destruction of pancreatic beta cells. This process is triggered, in part, by specific (aa 9-23) epitopes of the insulin Β chain. Previously, fish insulins were used clinically in patients allergic to bovine or porcine insulin. Fish and human insulin differ by two amino acids in the critical immunogenic region (aa 9-23) of the B chain. We hypothesized that β cells synthesizing fish insulin would be less immunogenic in a mouse model of T1D. Transgenic NOD mice in which Greater Amberjack fish (Seriola dumerili) insulin was substituted for the insulin 2 gene were generated (mouse Ins1 mouse Ins2 fish Ins2). In these mice, pancreatic islets remained free of autoimmune attack. To determine whether such reduction in immunogenicity is sufficient to protect β cells from autoimmunity upon transplantation, we transplanted fish Ins2 transgenic (expressing solely Seriola dumerili Ins2), NOD, or B16:A-dKO islets under the kidney capsules of 5 weeks old female NOD wildtype mice. The B:Y16A Β chain substitution has been previously shown to be protective of T1D in NOD mice. NOD mice receiving Seriola dumerili transgenic islet transplants showed a significant (p = 0.004) prolongation of their euglycemic period (by 6 weeks; up to 18 weeks of age) compared to un-manipulated female NOD (diabetes onset at 12 weeks of age) and those receiving B16:A-dKO islet transplants (diabetes onset at 12 weeks of age). These data support the concept that specific amino acid sequence modifications can reduce insulin immunogenicity. Additionally, our study shows that alteration of a single epitope is not sufficient to halt an ongoing autoimmune response. Which, and how many, T cell epitopes are required and suffice to perpetuate autoimmunity is currently unknown. Such studies may be useful to achieve host tolerance to β cells by inactivating key immunogenic epitopes of stem cell-derived β cells intended for transplantation.
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http://dx.doi.org/10.1038/s41598-019-40768-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428854PMC
March 2019

A role for foregut tyrosine metabolism in glucose tolerance.

Mol Metab 2019 05 27;23:37-50. Epub 2019 Feb 27.

Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA. Electronic address:

Objective: We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion.

Methods: To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge.

Results: We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation.

Conclusions: We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.
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http://dx.doi.org/10.1016/j.molmet.2019.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479665PMC
May 2019

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development.

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Naomi Berrie Diabetes Center & Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.

Intronic polymorphisms in the α-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.
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http://dx.doi.org/10.1172/jci.insight.123337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413800PMC
February 2019

Resistance Training Reduces Skeletal Muscle Work Efficiency in Weight-Reduced and Non-Weight-Reduced Subjects.

Obesity (Silver Spring) 2018 10 27;26(10):1576-1583. Epub 2018 Sep 27.

Division of Endocrinology, Diabetes, & Metabolism, New York Weill Cornell Medical Center Comprehensive Weight Control Center, New York, New York, USA.

Objective: The objective of this study is to determine whether resistance training is similarly effective in reducing skeletal muscle efficiency and increasing strength in weight-reduced and maximal weight subjects.

Methods: This study examined the effects of supervised resistance exercise on skeletal muscle in 14 individuals with overweight and obesity sustaining a 10% or greater weight loss for over 6 months and a phenotypically similar group of 15 subjects who had not reduced weight and were weight stable at their maximal lifetime body weight. We assessed skeletal muscle work efficiency and fuel utilization (bicycle ergometry), strength (dynamometry), body composition (dual energy x-ray absorptiometry), and resting energy expenditure (indirect calorimetry) before and after 12 weeks of thrice-weekly resistance training.

Results: Non-weight-reduced subjects were significantly (10%-20%) stronger before and after the intervention than reduced-weight subjects and gained significantly more fat-free mass with a greater decline in percentage of body fat than weight-reduced subjects. Resistance training resulted in similar significant decreases (~10%) in skeletal muscle work efficiency at low-level exercise and ~10% to 20% increases in leg strength in both weight-reduced and non-weight-reduced subjects.

Conclusions: Resistance training similarly increases muscle strength and decreases efficiency regardless of weight loss history. Increased resistance training could be an effective adjunct to reduced-weight maintenance therapy.
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http://dx.doi.org/10.1002/oby.22274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905638PMC
October 2018

Pancreatic Beta Cell Differentiation From Human Pluripotent Stem Cells.

Curr Protoc Hum Genet 2018 10 7;99(1):e68. Epub 2018 Sep 7.

Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York.

Insulin-expressing beta cells are crucial for the maintenance of systemic glucose homeostasis. Elucidation of the molecular and cellular mechanisms of beta cell development, expansion, survival, and function are required for full understanding of the molecular pathogenesis of diabetes. However, access to human beta cells for such studies is limited by virtue of the logistics of acquisition, prior medical status of donor, and imperfect culture systems for maintaining beta cell identity and function after isolation from human pancreas. Here, a technique for generation of beta cells from human pluripotent stem cells (hPSCs) by modification of key signaling pathways during islet development is described. Up to 70% C-peptide-positive beta cells can be obtained from endodermal anlagen after 27 days of differentiation with specific growth factors and small molecules. Although 50% of them are monohormonal C-peptide-positive cells and have molecular and cellular characteristics consistent with human beta cells in the Islets of Langerhans, a sub-population co-expressing other endocrine markers are also generated, indicating the immaturity of these cells. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cphg.68DOI Listing
October 2018

Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?

J Clin Invest 2018 08 16;128(8):3237-3239. Epub 2018 Jul 16.

Brown et al. report that two weeks of exogenous leptin administration to leptin-naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions.
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http://dx.doi.org/10.1172/JCI122042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063491PMC
August 2018

The Carbohydrate-Insulin Model of Obesity Is Difficult to Reconcile With Current Evidence.

JAMA Intern Med 2018 08;178(8):1103-1105

Columbia University, New York, New York.

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http://dx.doi.org/10.1001/jamainternmed.2018.2920DOI Listing
August 2018

FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications.

J Lipid Res 2018 08 22;59(8):1446-1460. Epub 2018 Jun 22.

Columbia University Medical Center, New York, NY 10032.

SNPs in the first intron of α-ketoglutarate-dependent dioxygenase () convey effects on adiposity by mechanisms that remain unclear, but appear to include modulation of expression of itself, as well as other genes in expression is lower in fibroblasts and iPSC-derived neurons of individuals segregating for obesity risk alleles. We employed in vitro adipogenesis models to investigate the molecular mechanisms by which Fto affects adipocyte development and function. expression was upregulated during adipogenesis, and was required for the maintenance of and / expression in murine and human adipocytes in vitro. knockdown decreased the number of 3T3-L1 cells that differentiated into adipocytes as well as the amount of lipid per mature adipocyte. This effect on adipocyte programming was conveyed, in part, by modulation of CCAAT enhancer binding protein (C/ebp)β-regulated transcription. We found that Fto also affected transcription by demethylating DNA N6-methyldeoxyadenosine in the promoter. Fto is permissive for adipogenesis and promotes maintenance of lipid content in mature adipocytes by enabling C/ebpβ-driven transcription and expression of These findings are consistent with the loss of fat mass in mice segregating for a dominant-negative allele.
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http://dx.doi.org/10.1194/jlr.M085555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071765PMC
August 2018
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