Congrats to Rafael yet again on the publication of our paper in Journal of Clinical Investigation this month! In this paper we identify alterations in serotonin-dependent signaling as a potential contribution to post-bariatric hypoglycemia. We thank the entire research team and our volunteers who give so generously of their time and blood samples to find new approaches to treat hypoglycemia!
Congrats to Rafael again! His paper describing metabolic effects of protein vs. caloric restriction in human studies performed during his PhD work was just published in Nutrients!
Congratulations to postdoc Rafael Ferraz Bannitz PhD for being selected as a winner of the poster session at the the poster session at the BIDMC Translational Research Hub meeting last Thursday!
Congratulations to postdoc Arionas Efthymiou PhD for being chosen to deliver an oral short talk at the upcoming BAT meeting in Copenhagen and an oral poster at the American Diabetes Association Scientific Sessions in New Orleans (June 2022)!
Hooray for Erika! We are so excited to announce that lab manager Erika Pacheco was accepted into the New England College of Optometry, to begin this fall. We are sad to see her go but happy she has achieved the next step of her goals!
Newly accepted manuscripts from the Patti Lab:
New review from Dr. Xuehong Dong and Dr. Lei Su (former postdocs) - in press
New review from Dr. Arionas Efthymiou (Postdoctoral Fellow in Patti Lab) - Congratulations!
Efthymiou A, Patti ME. It’s Not Just Fat: Dissecting the Heterogeneity of Adipose Tissue Function. Current Diabetes Reports, in press, 2022.
Congratulations to Chisayo Kozuka, former postdoctoral fellow in Patti Lab, and many others, on acceptance of a new paper identifying a new epigenetic regulatory mechanism contributing to glucose control in the journal Diabetes!
Kozuka C, Sales V, Osataphan S, Yuchi Y, Chimene-Weiss, Mulla C, Isganaitis E, Desmond J, Sanechika S, Kusuyama J, Goodyear L, Shi X, Gerszten RE, Wu L, Qi J, Patti ME. Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control. Biorxiv doi: https://doi.org/10.1101/2019.12.11.872887. In press, Diabetes, 2022. PMID: 35100352
Graphical abstract:
Abstract: Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate that Brd4 binds to the promoter region of FGF19 in human intestinal cells; BRD inhibition by JQ-1 reduces binding to the FGF19 promoter and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver, and a contributor to the gut-liver axis and systemic glucose metabolism.
Press release for new publication from Patti Lab in Nature Communications:
Dreyfuss JM, Yuchi Y, Pan H, Dong X, Simonson DC, Vernon A, Aryal P, Konkar A, Sebastian Y, Higgs BW, Grimsby J, Rondinone CM, Kasif S, Kahn BB, Foster K, Goldfine AB, Patti ME. Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery. bioRxiv 817494; doi: https://doi.org/10.1101/817494, Nature Communications 2021 Nov 29;12(1):6951. doi: 10.1038/s41467-021-27289-2. PMID:34845204. PMCID: PMC8630169.
How Stomach Surgery Makes the Cut for Diabetes
November 29, 2021
Studying molecular factors that mediate bariatric surgery’s beneficial effect on type 2 diabetes, Joslin investigators identify one that could be targeted therapeutically without surgery.
More than a quarter of a million people undergo bariatric surgery each year in the United States. Around 90% of those with type 2 diabetes who undergo gastric bypass, a procedure that restructures the stomach, successfully remove their elevations in blood glucose levels after a year, and half of that group maintains this state of remission for five years.
Weight loss is only part of the recipe for success—even before they start losing weight, patients experience changes in metabolism that help them maintain normal levels of blood glucose. So what drives those changes?
Using a powerful new statistical tool to analyze the results of a pioneering clinical trial, Joslin Diabetes Center researchers have identified molecular factors that may be key to achieving improved glucose control after bariatric surgery. Among the factors, levels of a protein called growth hormone receptor (GHR) in the blood of patients with type 2 diabetes are a surprisingly strong mediator of clinical benefit—more statistically significant, in fact, than weight loss.
A better understanding of such metabolic factors eventually may make it possible to deliver the benefits of bariatric surgery without actual procedures. "It would be nice to get these changes affecting glucose metabolism without having to cut someone open," said Jonathan Dreyfuss, PhD, Director of Joslin's Bioinformatics & Biostatistics Core and co-lead-author on a Nature Communications paper presenting the research. "We want to devise new strategies for medical management to improve our care, harnessing the effects of the surgery in non-surgical methods," said Mary-Elizabeth Patti, MD, a Joslin principal investigator and corresponding author on the paper.
The research builds on SLIMM-T2D (Surgery or Lifestyle with Intensive Medical Management in the Treatment of Type 2 Diabetes), a clinical trial co-led by Joslin and Brigham and Women's Hospital.
The group of people with type 2 diabetes who choose bariatric surgery is often quite distinct from those who don't, which limits what can be learned from population studies of people who get the surgery, Patti noted. But SLIMM-T2D was a randomized trial, dividing patients into two groups that were given either medical therapy or a well-established form of bariatric surgery known as Roux-en-Y gastric bypass.
"Randomization allowed us to examine the differences between medical therapy and surgery in a precise way that we can't achieve from population-based studies," she said.
Patti and her colleagues compared weight loss, hemoglobin A1C measurements (which reflect blood glucose levels) and levels of proteins and metabolites (body chemicals involved in metabolism) in blood samples gathered from the two groups in the SLIMM-T2D trial over time.
The statistical tool that Dreyfuss developed revealed that the growth hormone receptor (GHR) protein, which enables signaling by the growth hormone protein, was the lead mediator of improvements in glucose levels.
As its name suggests, growth hormone is a key molecular player for growth during childhood and puberty. The hormone also plays important metabolic roles in adults, among them countering the impact of insulin on blood glucose, Patti said. That is, if glucose levels drop, the growth hormone pathway can kick in and help to boost glucose.
"Here we have the first data that surgery may actually reduce growth hormone signaling and thus contribute to reduction in glucose," Patti said. "That makes sense, but it wasn't something that was on people's radars as a mechanism for the effects of bariatric surgery."
Among other findings from SLIMM-T2D, the team showed that surgery dramatically altered the levels of a group of metabolites called "branched-chain amino acids". This discovery was consistent with previous evidence that these metabolites are important in diabetes-related metabolism, said Patti.
Her team followed up with studies in animal models to see if those models would exhibit corresponding mechanisms for GHR metabolism. Among the supporting evidence, the scientists found, genetically modifying mouse liver cells to decrease the production of GHR also decreased glucose production. Similarly, the production of GHR dropped in the livers of rats that underwent bariatric surgery.
Patti and her team plan to follow up with other research in animal models to probe the molecular pathways triggered by GHR mechanisms.
In the meantime, she emphasized, "many people with type 2 diabetes, especially early in the course of the disease, should think about bariatric surgery as a treatment approach."
"Not everyone wants surgery and not everyone can get surgery," Patti added. "It's not an easy thing to go through, it takes a lot of work, and it's a challenging approach. But it has very durable long-term effects."
SLIMM-T2D was a partnership between Joslin diabetes experts and surgeons at Brigham and Women's Hospital, while the analysis and validation of its protein and metabolite measurements was a joint effort between bioinformatics and laboratory science at Joslin. "When our target is a clinical disease, we need people with different expertise, different areas of interest and different focuses to work together," she said. "This is an example of how Joslin allows cross-disciplinary collaboration to occur easily."
Yixing Yuchi of Joslin was co-lead-author on the paper. Other Joslin contributors included Xuehong Dong, Vissarion Efthymiou, Hui Pan, Kathleen Foster and Allison Goldfine. Co-authors also included Donald Simonson, Ashley Vernon, Florencia Halperin, Pratik Aryal and Barbara Kahn of Harvard Medical School; Anish Konkar, Yinong Sebastian, Brandon Higgs, Joseph Grimsby and Cristina Rondinone of MedImmune; Simon Kasif of Boston University; Randy Seeley of the University of Michigan; and Vera Djordjilović of the University of Venice. Lead funding came from the National Institutes of Health, the Charles King Trust and the Patient-Centered Outcomes Research Institute. MedImmune provided an unrestricted investigator-initiated research grant for assays.
https://www.joslin.org/about/news-media/how-stomach-surgery-makes-cut-di...
Paternal BMI Affects Infants' Birth Weight
Press release for new publication:
Noor N, Cardenas A, Rifas- Shiman SL, Pan H, Dreyfuss JM, Oken E, Hivert MF, James-Todd T, Patti ME, Isganaitis E. Peri-conception paternal BMI is associated with persistent changes in offspring DNA methylation in humans. JAMA Netw Open. 2019 Dec 2;2(12):e1916777.
https://catalyst.harvard.edu/news/article/paternal-bmi-affects-infants-b...
Interview with:
Elvira Isganaitis, MD, MPH, pediatric endocrinologist, Joslin Diabetes Center; assistant professor of pediatrics, Harvard Medical School
What is the background for this study?
Response: The concept that a mother’s nutrition prior to and during pregnancy is important for health outcomes in the offspring is now well accepted. For example, women intending to get pregnant must take prenatal vitamins, and are encouraged to attain a healthy weight before conception. However, much less is known about how a father’s nutritional status may influence childhood health outcomes. Based on studies in animals, exposure to undernutrition, high-fat diet, or stressful experiences in fathers can result in increased risk of obesity and diabetes in the offspring. These effects are mediated in part by epigenetic mechanisms (i.e. changes in gene expression due to differences in DNA methylation, histones, or other non-genetic mechanisms).
What are the main findings?
Response: In this study, we examined whether father’s weight status (body mass index) at the time of conception was associated with epigenetic marks and weight status in the offspring. We found that father’s BMI was associated with infant birth weight and with DNA methylation at several genetic loci in the offspring. Importantly, these associations remained significant after adjusting for multiple potential confounders such as maternal BMI, age, pregnancy complications, socioeconomic factors, smoking, etc.
What should readers take away from your report?
“The health of both parents (not just the mother) may influence childhood health outcomes.”
Response: The health of both parents (not just the mother) may influence childhood health outcomes. Our data add to the emerging body of evidence pointing to effects of paternal risk factors on pediatric health. For example, there are data linking increasing paternal age to risk of autism, and several studies have shown that paternal type 1 diabetes increases risk of childhood diabetes to a greater extent than maternal type 1 diabetes.
What recommendations do you have for future research as a result of this work?
Response: As these data were based on a population cohort in the Boston area (Project Viva), it will be important to verify whether these associations are reproduced in other populations.
An exciting possibility that is raised by these data is that preconception interventions in fathers could provide a novel approach to improve health outcomes in the next generation.
Is there anything else you would like to add?
Response: This type of research is only possible through collaborations. Co-authors included: Nudrat Noor, PhD1,2; Andres Cardenas, PhD, MPH3,4; Sheryl L. Rifas-Shiman, MPH3; Hui Pan, PhD5; Jonathan M. Dreyfuss, PhD5; Emily Oken, MD, MPH3,6; Marie-France Hivert, MD3; Tamarra James-Todd, PhD1,2; Mary-Elizabeth Patti, MD5,7
1Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
3Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
4Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley
5Research Division, Joslin Diabetes Center, Boston, Massachusetts
6Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
7Department of Medicine, Harvard Medical School, Boston, Massachusetts
8Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
Funding/Support: This work was conducted with support from Harvard Catalyst: The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. This study was funded by National Institutes of Health grants R01 HD034568 and UH3 OD023286 (funding for Project Viva), R21 HD091974 (Drs Isganaitis and Patti), P30 DK036836 (to Joslin Diabetes Center, Diabetes Research Center Award), R01 DK105193 (Dr Patti), P30 ES000002 (Dr James-Todd), and T32 ES007069 (Dr Noor). Grants R01 HL111108 and R01 NR013945 from the National Institutes of Health funded the DNA methylation analyses.
Conflict of Interest Disclosures: Ms Rifas-Shiman reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Oken reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Patti reported receiving grants from the National Institutes of Health, research grants from Xeris and Dexcom, personal fees from Fractyl, Eiger Pharmaceuticals, and Avolynt, and research supplies from Insulet during the conduct of the study, all outside the submitted work. Dr Isganaitis reported receiving grants from the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and AstraZeneca during the conduct of the study. No other disclosures were reported.
Citation:
Noor N, Cardenas A, Rifas-Shiman SL, et al. Association of Periconception Paternal Body Mass Index With Persistent Changes in DNA Methylation of Offspring in Childhood. JAMA Netw Oen. 2019;2(12):e1916777. doi:https://doi.org/10.1001/jamanetworkopen.2019.16777
Originally published on MedicalResearch.com
