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Reducing endocannabinoid system’s activity may help protect the kidney health of individuals with obesity

07/09/2017

New study provides insight on the mechanisms behind the development of kidney damage due to obesity, points to a potential target for protecting the kidney health of individuals with obesity

Highlights: Structural and functional changes in the kidneys develop early in the course of obesity. A particular receptor in kidney cells plays an important role in obesity-induced fat accumulation, dysfunction, injury, inflammation, and scarring in the kidney. The receptor acts through a certain signaling pathway. Targeting this receptor or the signaling pathway may help protect the kidneys of individuals who develop obesity.

Jerusalem, September 6, 2017 — A new study provides insights on the mechanisms behind the development of kidney damage due to obesity. The findings, which appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN), point to a potential target for protecting the kidney health of individuals with obesity.

Obesity-related kidney dysfunction develops early in the course of obesity, justifying the search for novel regulators that could be targeted for therapy. Obesity can cause structural and functional changes in the kidneys, which may help explain why individuals with obesity face an elevated risk of chronic kidney disease and its progression to kidney failure. Although multiple metabolic factors have been proposed to contribute to obesity-induced kidney problems, the underlying mechanisms are not completely understood.

To investigate, a team led by Dr. Joseph (Yossi) Tam, DMD, PhD and the PhD student Shiran Udi, MSc, at the Hebrew University of Jerusalem’s Institute for Drug Research in Israel, examined the kidney cells that are responsible for the reabsorption of nutrients, while allowing other substances of no nutritional value to be excreted in the urine. These kidney cells, called renal proximal tubular cells or RPTCs, are especially sensitive to the accumulation of fat, or lipids — an effect called lipotoxicity.

The researchers examined the potential role of endocannabinoids, lipid molecules that interact with the cannabinoid-1 receptor (CB1R) and are abundantly expressed in the brain and periphery, including the kidney. Endocannabinoids act on the CB1R receptor in RPTC renal cell lipotoxicity. Mice that lacked expression of the receptor in the RPTC renal cells experienced significantly less obesity-induced lipid accumulation in the kidney as well as less kidney dysfunction, injury, inflammation, and scarring.

Moreover, the study revealed the molecular signaling pathway involved in mediating the kidney injury and lipotoxicity in RPTC renal cells induced by the CB1R cellular receptors. Specifically, these deleterious effects associated with decreased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as reduced fatty acid β-oxidation.

The research shows that manipulating the cannabinoid-1 receptor (CB1R) specifically in the RPTC renal cells may provide a novel therapeutic intervention for treating obesity-induced nephropathy.

“This work provides a novel approach to slow the development of renal injury through chronic blockade of peripheral CB1Rs,” said Dr. Tam. “It also supports strategies aimed at reducing the activity of the endocannabinoid system, specifically in the kidney, to attenuate the development of RPTC dysfunction in obesity.”

Study co-authors include Liad Hinden, PhD, Brian Earley, MSc, Adi Drori, PhD, Noa Reuveni, Rivka Hadar, MSc, Resat Cinar, PhD, and Alina Nemirovski, PhD.  Dr. Tam is Director of the Hebrew University’s Multidisciplinary Center on Cannabinoid Research (http://cannabinoids.huji.ac.il), and Head of the Obesity and Metabolism Laboratory at the Hebrew University’s Institute for Drug Research in the Faculty of Medicine.

FUNDING: The work was supported by a German-Israeli Foundation grant (#I-2345-201.2/2014), and an ERC-2015-StG grant (#676841) to Dr. Joseph Tam.

CITATION: Shiran Udi, Liad Hinden et al. Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD. Published online before print August 31, 2017. Journal of the American Society of Nephrology (JASN), doi: 10.1681/ASN.2016101085, http://jasn.asnjournals.org/content/early/2017/08/30/ASN.2016101085

Reducing endocannabinoid system’s activity may help protect the kidney health of individuals with obesity
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Higher BMI in Adolescence May Affect Cognitive Function in Midlife

11/12/2016

Study of Israeli adolescents also looks at impact of socioeconomic position on subsequent cognitive impairment

Overweight and obesity in adolescents have increased substantially in recent decades, and today affect a third of the adolescent population in some developed countries. While the dangers posed by high adult BMI on cognitive function in later life have been documented, the association of adolescent BMI with cognitive function in midlife has not yet been reported. (BMI, or Body Mass Index, is a calculation of a person’s weight in kilograms divided by the square of their height in meters.)

To shed light on this issue, scientists at the Hebrew University-Hadassah Braun School of Public Health and Community Medicine set out to determine the association between cumulative life course burden of high-ranked body mass index (BMI), and cognitive function in midlife. The research, which will appear in the Journal of Alzheimer’s Disease 55(3), was led by Prof. Jeremy Kark from the Braun School, in the Hebrew University of Jerusalem’s Faculty of Medicine, working with colleagues in Israel and the United States.

The researchers used weight and height data from 507 individuals tracked from over 33 years starting at age 17. The participants completed a computerized cognitive assessment at ages 48–52, and their socioeconomic position was assessed by multiple methods. Using mixed models the researchers calculated the life-course burden of BMI from age 17 to midlife, and used multiple regression to assess associations of BMI and height with global cognition and its five component domains.

In this population-based study of a Jerusalem cohort, followed longitudinally from adolescence for over 33 years, we found that higher BMI in late adolescence and the long-term cumulative burden of BMI predicted poorer cognitive function later in life. Importantly, this study shows that an impact of obesity on cognitive function in midlife may already begin in adolescence, independently of changes in BMI over the adult life course,” said the paper’s senior author, Prof.  Jeremy Kark of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine.

“Our results also show that taller stature was associated with better global cognitive function, independent of childhood and adult socioeconomic position, and that height increase in late adolescence, reflecting late growth, conferred a protective effect, but among women only,” added Irit Cohen-Manheim, doctoral candidate at the Braun School and lead author.

The researchers point out that while socioeconomic position may have a particularly important role in the trajectory of a person’s lifetime cognitive function, it has rarely been adequately taken into account: “To the best of our knowledge, the association between BMI and cognition as a function of childhood and adult socioeconomic position has not been previously reported. Childhood household socioeconomic position appears to strongly modify the association between adolescent BMI and poorer cognition in midlife, the inverse association being restricted to low childhood socioeconomic position,” said Prof. Kark.

"Our results are consistent with the hypothesis that childhood living conditions, as reflected also by height, influence cognitive function later in life; however, our study is unique in showing that an adverse association of higher BMI with cognitive function appears to begin in adolescence and that it appears to be restricted to adults with lower childhood socioeconomic position,” said Prof.  Kark.

Evidence for the association between impaired cognitive function in midlife and subsequent dementia supports the clinical relevance of our results. Findings of the relation of BMI in adolescence with poorer midlife cognitive status, particularly in light of the ongoing epidemic of childhood obesity, require confirmation," said Irit Cohen-Manheim.

Scientists involved in this research are affiliated with the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel; Department of Clinical Research, NeuroTrax Corporation, Modiin, Israel; Centre for Medical Decision Making, Ono Academic College, Kiryat Ono, Israel; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Biostatistics Unit, Gertner Institute for Epidemiology and Health Policy Research, Tel-Hashomer, Israel.

FUNDING: The research was supported by grants from the Chief Scientist of the Israel Ministry of Health, the Israel Science Foundation, and the US-Israel Binational Science Foundation to Prof. Jeremy Kark.

REFERENCE: Irit Cohen-Manheim, Glen M. Doniger, Ronit Sinnreich, Ely S. Simon, Havi Murad, Ronit Pinchas-Mizrachi and Jeremy D. Kark. Body Mass Index, Height, and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife. The Journal of Alzheimer's Disease 55(3), article pre-published on December 6, 2016, DOI: 10.3233/JAD-160843.

The Hebrew University of Jerusalem is Israel’s leading academic and research institution, producing one-third of all civilian research in Israel. For more information, visit http://new.huji.ac.il/en.

Higher BMI in Adolescence May Affect Cognitive Function in Midlife
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Increased BMI During Adolescence Predicts Fatal Cardiovascular Events In Adulthood

14/04/2016
Nationwide study of 2.3 million Israeli adolescents examined from 1967 through 2010 finds association between elevated BMI in late adolescence and subsequent cardiovascular mortality in midlife

Overweight and obesity in adolescents have increased substantially in recent decades, and currently affect a third of the adolescent population in some developed countries. This is an important public health concern because obesity early in life is considered to be a risk factor for death from cardiovascular disease and from all causes in adulthood.

Some studies suggest that an elevated body-mass index is associated with an increased risk of death from cardiovascular causes. However, a determination of the BMI threshold that is associated with increased risk of fatality remains uncertain. (BMI is a calculation of a person’s weight in kilograms divided by the square of their height in meters, to quantify body mass and enable categorization as underweight, normal weight, overweight, or obese.)

In light of the worldwide increase in childhood obesity, Prof. Jeremy Kark from the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, in the Hebrew University of Jerusalem’s Faculty of Medicine, together with Dr. Gilad Twig of Sheba Medical Center, and Dr. Hagai Levine also of the Braun School of Public Health and other colleagues in Israel, set out to determine the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood.

Their study, which appears in The New England Journal of Medicine, was based on a national database of 2.3 million Israeli 17 year olds in whom height and weight were measured between 1967 and 2010. The researchers assessed the association between BMI in late adolescence and death from coronary heart disease, stroke, and sudden death in adulthood by mid-2011.

During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death.

The results showed an increase in the risk of cardiovascular death in the group that was considered within the “accepted normal” range of BMI, in the 50th to 74th percentiles, and of death from coronary heart disease at BMI values above 20. The researchers concluded that even BMI considered “normal” during adolescence was associated with a graded increase in cardiovascular and all-cause mortality during the 40 years of follow-up. This included increased rates of death from coronary heart disease, stroke, and total cardiovascular causes among participants.

As BMI scores increased into the 75th to 84th percentiles, adolescent obesity was associated with elevated risk of death from coronary heart disease, stroke, sudden death from unknown causes, and death from total cardiovascular causes, as well as death from non-cardiovascular causes and death from all causes. Participants also had an increased risk of sudden death.

The rates of death per person-year were generally lowest in the group that had BMI values during adolescence in the 25th to 49th percentiles, although higher rates were observed among those below the 5th percentile.

How might adolescent BMI influence cardiovascular outcomes in adulthood? The researchers considered two possible pathways. First, obesity may be harmful during adolescence, since it has been associated with unfavorable metabolic abnormalities through risk factors such as unfavorable plasma lipid or lipoprotein levels, increased blood pressure, impaired glucose metabolism, insulin resistance, and formation of coronary and aortic atherosclerotic plaques. Furthermore, the timing of exposure to obesity during a person's lifetime may play an important role. Second, BMI tends to "track' along the life course so that overweight adolescents tend to become overweight or obese adults, and overweight or obesity in adulthood affects the risk of cardiovascular disease.

“Our findings appear to provide a link between the trends in adolescent overweight during the past decades and coronary mortality in midlife,” said the paper’s senior author, Prof.  Jeremy Kark of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine. “The continuing increase in adolescent BMI, and the rising prevalence of overweight and obesity among adolescents, may account for a substantial and growing future burden of cardiovascular disease, particularly coronary heart disease.”

Scientists involved in this research are affiliated with the Department of Medicine and the Dr. Pinchas Bornstein Talpiot Medical Leadership Program, Sheba Medical Center; Israel Defense Forces Medical Corps; Sackler School of Medicine, Tel Aviv University; Hebrew University-Hadassah Braun School of Public Health and Community Medicine; Israel Ministry of Health; Department of Medicine, Mount Auburn Hospital; and Harvard Medical School.

FUNDING: The study was funded by a research grant from the Environment and Health Fund in Jerusalem

REFERENCE: Gilad Twig, Gal Yaniv, Hagai Levine, Adi Leiba, Nehama Goldberger, Estela Derazne, Dana Ben‑Ami Shor, Dorit Tzur, Arnon Afek, Ari Shamiss, Ziona Haklai, and Jeremy D. Kark. Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood. The New England Journal of Medicine, published on April 13, 2016, at NEJM.org. DOI: 10.1056/NEJMoa1503840. LINK: http://www.nejm.org/doi/full/10.1056/NEJMoa1503840

The Hebrew University of Jerusalem is Israel’s leading academic and research institution, producing one-third of all civilian research in Israel. For more information, visit http://new.huji.ac.il/en.

Increased BMI During Adolescence Predicts Fatal Cardiovascular Events In Adulthood
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