Chelsea DeLeon
May 1, 2020; 61:767-777
Research Articles

Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkβ1^–/–), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iβ1β2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkβ1^–/– hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkβ1^–/–, AccDKI, and iβ1β2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms.

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

Obesity has recently become a prevalent health threat worldwide. Although emerging evidence has suggested a strong link between the pentose phosphate pathway (PPP) and obesity, the role of transketolase (TKT), an enzyme in the non-oxidative branch of the PPP which connects PPP and glycolysis, remains obscure in adipose tissues. In this study, we specifically delete TKT in mouse adipocytes and find no obvious phenotype upon normal diet feeding. However, adipocyte TKT abrogation attenuates high fat diet (HFD)-induced obesity, reduces hepatic steatosis, improves glucose tolerance, alleviates insulin resistance and increases energy expenditure. Mechanistically, TKT deficiency accumulates non-oxidative PPP metabolites, decreases glycolysis and pyruvate input into the mitochondria, leading to increased lipolytic enzyme gene expression and enhanced lipolysis, fatty acid oxidation and mitochondrial respiration. Therefore, our data not only identify a novel role of TKT in regulating lipolysis and obesity, but also suggest limiting glucose-derived carbon into the mitochondria induces lipid catabolism and energy expenditure.

Obesity is a risk factor for type 2 diabetes (T2D), however not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from T2D and non-T2D (ND) especially obese donors (BMI ≥30 kg/m²). Islets from obese T2D donors had reduced insulin secretion, decreased β-cell exocytosis and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis and reduced granule docking. This was accompanied with reduced expression of the exocytotic proteins, SNAP25, STXBP1 and VAMP2, likely because CD36 induced down-regulation of the IRS proteins, suppressed insulin signaling PI3K-AKT pathway and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human β-cell line, EndoC-βH1, increased IRS1 and exocytotic protein levels, improved granule docking and enhanced insulin secretion. Our results demonstrate that β-cells from obese T2D donors have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit β-cell function in T2D associated with obesity.

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

Rhian M. Touyz
Jan 1, 2016; 65:19-21
Commentaries

2 May 2019 , Volume 95, Number 3

12 June 2019

Research Event

Event participants

Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House
Joanne Neenan, Legal Adviser, UK Foreign and Commonwealth Office
Darren Stewart, Head of Operational Law, UK Army Headquarters
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

27 June 2019

Siege warfare has been employed throughout the ages and remains dramatically relevant today. Questions of the compatibility of this practice with international humanitarian law (IHL) arise when besieged areas contain civilians as well as enemy forces. This briefing addresses those rules of IHL that are particularly relevant to sieges. 

Members Event

Event participants

Professor Sarah Cleveland, Louis Henkin Professor of Human and Constitutional Rights; Faculty Co-Director, Human Rights Institute, Columbia Law School

Amal Clooney, Barrister, Doughty Street Chambers

The Honourable Irwin Cotler, Chair, Raoul Wallenberg Centre for Human Rights; Minister of Justice and Attorney-General of Canada (2003-06)

Baroness Helena Kennedy QC, Director, International Bar Association’s Human Rights Institute

Lord Neuberger, President, Supreme Court of the United Kingdom (2012-17)

Maria Ressa, CEO, Rappler Online News Network

Chair: Elizabeth Wilmshurst CMG, Distinguished Fellow, International Law Programme, Chatham House

The national priority at this time must be the protection of the Jamaican people against the onset of COVID-19. This has to be done by striking the balance between implementing protective public-health measures and providing a supporting economic...

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

With thousands more migrants potentially traveling through the Western Balkans this year, this MPI Europe webinar explores the implications of the buttressed EU border on the bloc’s neighbors, including the issues of outsourcing migration control, EU support for addressing irregular migration in neighboring countries, and considerations for EU policymakers.

With thousands migrants potentially traveling through the Western Balkans this year, this MPI Europe webinar explores the implications of the buttressed EU border on the bloc’s neighbors, the migrants transiting these routes, and the local communities. Experts also explored how the European Union can support efforts to address irregular migration in neighboring countries, and what are the tradeoffs and considerations that policymakers must weigh. 

The Trump administration’s decision to terminate the Deferred Action for Childhood Arrivals (DACA) deportation-relief program launched in 2012 has sparked new urgency to find a longer-term fix for "DREAMers," the unauthorized immigrants brought to the United States as children. This Policy Beat article examines movement in the courts and in Congress on the DREAM Act and similar proposals, exploring likely paths forward.

More than 51 million people worldwide are forcibly displaced today as refugees, asylum seekers, or internally displaced persons. This report details the increasing mismatch between the legal and normative frameworks that define the existing protection regime and the contemporary patterns of forced displacement.

MPI experts discuss the outcomes from the UN Summit on Large Movements of Refugees and Migrants and President Obama's Leaders Summit on the Global Refugee Crisis and what it means for international cooperation on refugee protection and management of migration flows.

Indonesia, which has a long history as a major origin for migrant labor in the Asia-Pacific and beyond, more recently has reluctantly found itself a transit and destination country, including for asylum seekers. Still, policymakers remain focused on protection of its nationals abroad rather than on assuring the status of Chinese and other foreigners in the country. This country profile explores Indonesia's rich migration history. 

A discussion, including the former United Nations Deputy High Commissioner for Refugees, examining the huge strains on the global protection system and how it can better respond to protracted refugee situations and other long-term displacement, focusing on the conclusions of the Transatlantic Council on Migration's recent meeting, Beyond Asylum: Rethinking Protection Policies to Meet Sharply Escalating Needs.

As the Trump administration weighs the future of Temporary Protected Status (TPS) for Salvadorans, this teleconference focuses on the legal framework for TPS (particularly for Hondurans and Salvadorans) and profile of current TPS holders; the capacity of El Salvador and Honduras to receive and meaningfully reintegrate returnees; and the implications of TPS termination for broader U.S. policy goals in Central America.

Employees at an Oregon restaurant said a peacock has taken on the role of protector for a mother duck and the eggs she laid in the closed patio area.

Ele Ferrannini
Jul 1, 2016; 39:1108-1114
Diabetes Care Symposium

MPI and MPI Europe experts discuss the effects of the coronavirus pandemic on asylum systems in Europe and North America, as well as in developing regions, where 85 percent of refugees live. During this freeform conversation, our analysts also assess the implications for the principle of asylum and the future for a post-World War II humanitarian protection system that is under threat.

Nearly 49% of responding dental practices have experienced employee theft, and nearly 46% of those have experienced theft or embezzlement more than once, according to a survey conducted by the ADA Council on Dental Practice.

The American Dental Association is urging the Centers for Disease Control and Prevention to provide immediate guidance on the best way to protect dental patients and staff from the transmission of COVID-19 during emergency and urgent care situations.

The Association is waiting for clear guidance from the Small Business Administration on the best way to help dentists considering applying for Paycheck Protection Program 7(a) loans.

Dentists can apply for both Economic Injury Disaster Loans and Paycheck Protection Program 7(a) loans, the Small Business Administration told the American Dental Association on April 6.

The Small Business Administration said that as of April 16, the agency is unable to accept any new applications for the Paycheck Protection Program or the Economic Injury Disaster Loans due to a lack of funding.

Wisconsin dentists have answered the call for personal protective equipment by organizing drives and donating their surplus supplies to hospitals and urgent care facilities treating patients with COVID-19.

The U.S. Department of Labor announced April 20 that it is ending the temporary period of non-enforcement of paid leave protections under the Families First Coronavirus Response Act.

A recorded webinar will stream April 27 outlining the Association’s interim recommendation for personal protective equipment in dental settings as some states consider loosening social distancing mandates.

The House of Representatives passed a new coronavirus relief bill April 23 that calls for additional funding for federal loan programs to help businesses nationwide, including dental practices, recover from the economic fallout of the pandemic.

The Small Business Administration will resume accepting Paycheck Protection Program loan applications at 10:30 a.m. EST on April 27 from “approved lenders on behalf of any eligible borrower,” the agency said.

The Organized Dentistry Coalition is asking Congress for flexibility in the Paycheck Protection Program to allow dentists to purchase personal protective equipment as states begin the reopening phase of the COVID-19 pandemic.

More patient portals and electronic health records should enable users to create "proxy" accounts for nurses and home aids to prevent unintentional sharing of personal health details, researchers said Monday.

With the Trump administration having announced the end of the DACA program, Congress is facing growing calls to protect unauthorized immigrants who came to the U.S. as children. This fact sheet examines DREAM Act bills introduced in Congress as of mid-2017, offering estimates of who might earn conditional legal status—and ultimately legal permanent residence—based on educational, professional, and other requirements in the legislation.

Some nominally high-risk individuals may have a lower chance of developing dementia than once thought

-- Read more on ScientificAmerican.com

Seventeen years ago, a couple of criminologists at the University of Maryland published an interesting paper about the 1976 District ban on handguns -- a ban that was recently overturned by the Supreme Court on the grounds it was inimical to the constitutional right of Americans to bear arms to p...

Following the 2015­–16 crisis that saw record numbers of refugees arrive in Europe, policymakers have shown interest in creating managed, legal alternatives to the dangerous, unauthorized journeys many asylum seekers make. While these discussions should be informed by an understanding of current pathways and protection channels, it is "nearly impossible" to know how protection seekers enter and what legal channels are available to them, as this MPI Europe report explains.

Across Europe, grassroots efforts have emerged in the wake of crisis that draw members of the public into the process of receiving refugees and supporting their integration. This policy brief examines the many forms community-based or private sponsorship can take, what benefits such approaches may hold for European communities, and the tradeoffs policymakers face in their implementation.

Following the release of the mid-term review of the European Agenda on Migration, this webinar offers insights from EU Member States on how existing, new, and untapped legal pathways interact with other humanitarian policies, and fit into a larger protection strategy.

As EU Member States struggle to deliver on the European Union's call to expand channels for foreign workers, they should focus more on attracting the middle- and low-skilled third-country nationals needed by the labor market yet for whom few opportunities for admission exist. They also would do well to consider their migration policies in light of labor market, foreign policy, and development objectives, rather than as a means to reduce irregular migration, this report cautions.

MPI and MPI Europe experts discuss the effects of the coronavirus pandemic on asylum systems in Europe and North America, as well as in developing regions, where 85 percent of refugees live. During this freeform conversation, our analysts also assess the implications for the principle of asylum and the future for a post-World War II humanitarian protection system that is under threat.