Janos Zempleni, Ph.D.Dept. of Nutrition and Health Sciences, UNL

Nebraska Center for the Preventionof Obesity Diseases through

Dietary Molecules

NPOD Mission

It is the mission of NPOD to discover mechanisms through which dietary molecules prevent obesity-

related diseases, particularly cardiovascular disease and diabetes, and to devise intervention strategies

for the prevention of these diseases.

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

SignificanceObesity among U.S. Adults, CDC 2010

Age-adjusted percentage of adults aged ≥20 years with diagnosed diabetes, 2007

Significance (cont’d)

CDC

Significance (cont’d)Heart Disease hospitalization rates among U.S. Adults, CDC 2000 - 2006

NIH’s Response to this Crisis

NIH PA-11-165: “Heart failure demands more effective low-cost managementapproaches […] dietary factors and nutritional deficiencies are known tocause heart failure in humans as well.”

2011 NIH program announcements

NIH PA-11-170: “Type 2 diabetes studies should assess the mechanisms ofdevelopmental programming, epigenetic changes, genetic background,nutrition, the microbiome, and inflammation that lead to diabetes.”

NIH Strategic Plan for Obesity Research, 2011• Discover the biological mechanisms leading to obesity and related diseases• Train a multidisciplinary scientific workforce• Devise efficient, effective, and fast approaches to translation in medical

and community settings

NPOD is Unique

• Policies that Cause Health Disparities in Alaska Natives

• Fetal Programming• Molecular Basis of Human Disease• Cardiovascular Biology

Centers of Biomedical Research Excellence on

NPOD’s Map to Success

• Study section members• Obesity COBREs• Website

• Facebook

Nebraska Gateway for Nutrigenomics

• Founded in 2008• Retreats, seminar series• Collaborations across 17 units• Joint grant applications, including T32• Junior investigator pilot grant program• Strategic priority for NHS, CEHS, IANR/ARD, UNL

Mid-term goal: advance to Center status

Specific Aim 1

Establish an NPOD administrative core of personnel and programs that support and enhance the

Center’s research.

Administrative CoreAdministrative Core – the EdgeAdministrative Core

Administrative Core- Global Timeline -

Activity Year 1 Year 2 Year 3 Year 4 Year 5

Establish Administrative Core, including hiring a 0.5 FTE office assistant to assist the center manager

“Kick-Off” meeting

Activate user accounts for the Computational and Data Sharing Core; open Core for use

Research project funding (Cohort 1)

Renovate and open Epigenetics Core for use

Seminar series

March and September retreats

Complete Hire #1 (molecular geneticist)

Award one to two pilot grants (pre-tenure category)

Submit NIH T32 training grant application

Complete Hires #2 (pharmacology and biotransformation) and #3 (fetal programming and adult disease)

Award two pilot grants (pre-tenure category)

Award one pilot grant (multidisciplinary category)

Complete Hire #4 (epidemiology and genetics)

Award two pilot grants (pre-tenure category)

Cohort 1 project leaders graduates to R01 status

Research project funding (Cohort 2)

Complete Hire #5 (adipocyte differentiation)

Award one to two pilot grants (pre-tenure category)

Award one pilot grant (multidisciplinary category)

Develop/submit NIH P01 Applications

Develop/submit Phase II COBRE Application

Specific Aim 2

Develop a critical mass of faculty through the support of five thematically linked primary research

projects, a strong mentoring program for junior investigators, and through support of two essential research core facilities and a pilot grant program.

Center Projects

Identified through an open competition

SaraswathiViswanathan

Dmitri Fomenko

Samodha Fernando

Jennifer Wood

Regis Moreau

ω-3 fatty acids,pro-inflammatory processes,hyperlipidemia

Redox signaling,selenoproteins

Gut microbesignaling

Fetal programming,pro-inflammatory processes

Lipoic acid signaling,hyperlipidemia

Cardiovasculardisease and

diabetes

DIETARYMOLECULES

Tenure track appointments

Anti-lipemic Signaling Mechanisms ofR-α-Lipoic Acid (LA)

LA

Regis Moreau, Ph.D.

Assistant ProfessorDepartment of Nutrition and Health SciencesUniversity of Nebraska-Lincoln

Novel Molecular Targets of LA

Fibroblast growth factor-21 (FGF21) mediates the lipolytic properties of LA.(Tf = Transcription factor)

LA downregulates SREBP1c-mediated transcription of lipogenic genes through inactivation mTORC1 (mammalian target of rapamycin complex 1)

β-oxidationgenes

Tf

FGFR

1 β-K

loth

o

Fgf21

Tf

X5

FGF21LA

Liver Muscle

X6

SREBP1c

LA

ChREBP

Lipogenic genesACC, FAS, GPAT1, DGAT2

mTORC1 Rheb

TSC1/2

Liver

Experimental Models

• Fgfr1f/f/Cre mice lacking fibroblast growth factor-21 (FGF21) receptor

• Tsc1f/f/Cre mice constitutively expressing mammalian target of rapamycin complex 1 (mTORC1)

Gt(ROSA)26Sor Cre ESRTsc1

loxPloxP

Cre/ESR

+Tamoxifen

Tsc1 KO

loxP

Fgfr1 KO

Fgfr1

loxPGt(ROSA)26Sor Cre ESR

Cre/ESR

+Tamoxifen

Innovation• Shift from the current paradigm that LA acts as an antioxidant

• Novel lipid-lowering mechanisms of LA

Stimulation of lipid clearance

Downregulation of triglyceride synthesis

Outcome• Safe and economical alternative to current lipid-lowering therapies

• Mechanism-based rationale for clinical trials with LA

Redox Signaling and Selenoproteins Alter Diabetes Risk

Dmitri Fomenko, Ph.D.

Assistant ProfessorDepartment of Biochemistry and Redox Biology CenterUniversity of Nebraska-Lincoln

Redox stress, impaired H2O2

signaling

ER stress

Type I and II diabetes

Signals of the Gut Microbiome that Ameliorate the Obesity Phenotype

Samodha Fernando, Ph.D.

Assistant ProfessorDepartment of Animal ScienceUniversity of Nebraska-Lincoln

(www.genome.gov) Kinross et al. Genome Medicine 2011 3:14  

Fetal Programming of Cardiovascular Disease and Diabetes

Jennifer Wood, Ph.D.

Assistant ProfessorDepartment of Animal ScienceUniversity of Nebraska-Lincoln

Oviduct/ In vitro Environment

Uterine Environment

Placental FunctionOrgan Development

Cardiovascular DiseaseObesity/Diabetes

Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids

Saraswathi Viswanathan, Ph.D.

Assistant ProfessorDepartment of Internal Medicine/DEMUniversity of Nebraska Medical Center-Omaha

Anti-inflammatory Effects

Lipid-lowering Effects

-3 Fatty Acids(EPA & DHA)

CardioprotectiveEffects

Synergies Among Center Projects

Example 1: Lipoic acid is an ω-substituted fatty acidAre Moreau/Viswanathan looking at the samemechanism?

Example 2: The intake of lipoate, methyl donors, andfatty acids are distinct between enterotypesCollaborations of Fernando with Moreau, Wood,

and Viswanathan?

Mentoring Clusters

Moriyama

Benson

Kac

hman

Davis

PowersC

upp

Lewis

DussaultD

esou

za

Becker

LeeH

arsh

man

Zempleni

CahoonW

ilson

Pilot Grant Programs

• Pre-tenure faculty: $50k/year for 2 years Objective: Identify and prepare faculty for project leader slots Four candidates have been identified (3 UNL, 1 UNMC)

• Multidisciplinary grants: $100k/year for 2 years Objective: Stimulate multidisciplinary research; sustainability PI is a Center member, others may come from any IDeA state

• T32 Director’s responsibility Objective: Keep members involved; recruit high-quality students

and postdocs; faculty recruiting tool

Epigenetics Core

• Comprehensive service, including study designand data analysis

• Director, co-director, and staff have been identified• Space has been identified• Remodeling is within the NIH $300k allowance• Useful to all Center members

Computational and Data Sharing Core

• Existing center with offices in Lincoln and Omaha• Director and NPOD Liaison have been identified• Services will be tailored to meet NPOD needs• Free accounts to all Center members• Accounts available to external users• Networked with Epigenetics core• Pilot-tested by NGN faculty• Key to data and file sharing with collaborators, among

mentoring cluster members, and with public

Specific Aim 3

Increase research capacity through targeted recruitment of five researchers in areas key to

Center success.

Hire 1

Molecular Genetics (NHS, UNL)• Search is nearing completion• Number 1 ranked candidate has an exceptionally strong

research program in overeating and ER stress• Good opportunities for collaboration with the Redox

center and with Dmitri Fomenko

Hire 2

Pharmacology and Biotransformation of Dietary Molecules (UNL)• Dietary molecules are subject to biotransformation• Task force group of faculty from NHS and FST• Good opportunities for collaboration with any Center

member

Hire 3

Fetal Programming and Adult Disease (UNL)• Clusters of strength in various departments at UNL• Focus on ncRNA/miRNA in mammalian systems• NIH priority area• Tenure home in UNL’s Departments of Animal Science,

Biological Systems Engineering, Biochemistry, Nutrition and Health Sciences, or split appointment

Hire 4

Epidemiology and Genetics with Expertise in Genome-wide Association Studies (UNL)• Translation into human research• Access to human databases• Project leaders may test their hypothesis in human

populations• Strategic priority hire for NHS but also a good fit for

Statistics

Hire 5

Adipocyte Differentiation (UNL)• Dietary molecules that regulate the differentiation of

stem cells into adipocytes• Novel concept (NIH RFA-ES-11-010)• Cluster of investigators at UNL (Pannier, Schlegel,

Wang, Zempleni)• Tenure home in Animal Science, Biological Systems

Engineering, Biochemistry, Nutrition and Health Sciences, or split appointment

UNMC

• NPOD contacts Drs. Davis, Desouza, and Lewis• UNMC Dept. Heads and Div. Chiefs (Batra,

Kabanov, Zucker)• Drs. Viswanathan (project leader) and Mott (pilot

grant)• Coordinating Committee

Specific Aim 4

Graduate from IDeA program funding as a self-sustainable center of research excellence through

the development of program projects and collaborative research grants.

Strategies

• P01 grants (stimulated by pilot grant program)• MPI R01 grants (stimulated by pilot grant

program)• T32 training grants• Fees for core facilities• Donors?• NGN retreat: Bayer Health, Mead Johnson,

Campbell’s Soup, Kemin