title: Multigenerational Undernutrition Increases Susceptibility to Obesity and Diabetes that Is Not Reversed after Dietary Recuperation.
abstract: People in developing countries have faced multigenerational undernutrition and are currently undergoing major lifestyle changes, contributing to an epidemic of metabolic diseases, though the underlying mechanisms remain unclear. Using a Wistar rat model of undernutrition over 50 generations, we show that Undernourished rats exhibit low birth-weight, high visceral adiposity (DXA/MRI), and insulin resistance (hyperinsulinemic-euglycemic clamps), compared to age-/gender-matched control rats. Undernourished rats also have higher circulating insulin, homocysteine, endotoxin and leptin levels, lower adiponectin, vitamin B12 and folate levels, and an 8-fold increased susceptibility to Streptozotocin-induced diabetes compared to control rats. Importantly, these metabolic abnormalities are not reversed after two generations of unrestricted access to commercial chow (nutrient recuperation). Altered epigenetic signatures in insulin-2 gene promoter region of Undernourished rats are not reversed by nutrient recuperation, and may contribute to the persistent detrimental metabolic profiles in similar multigenerational undernourished human populations.
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia. Electronic address: anand.hardikar@ctc.usyd.edu.au.
authors.forename: Anandwardhan A
authors.initials: AA
authors.lastname: Hardikar
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia; National Center for Cell Science, Ganeshkhind Road, Pune 411007, India.
authors.forename: Sarang N
authors.initials: SN
authors.lastname: Satoor
authors.affiliation: Department of Physiology, DY Patil Medical College, DPU, Pimpri, Pune 411018, India; Department of Physiology, BJ Medical College, Pune 411011, India.
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Karandikar
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
authors.forename: Mugdha V
authors.initials: MV
authors.lastname: Joglekar
authors.affiliation: National Center for Cell Science, Ganeshkhind Road, Pune 411007, India.
authors.forename: Amrutesh S
authors.initials: AS
authors.lastname: Puranik
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
authors.forename: Wilson
authors.initials: W
authors.lastname: Wong
authors.affiliation: National Center for Cell Science, Ganeshkhind Road, Pune 411007, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: National Center for Cell Science, Ganeshkhind Road, Pune 411007, India; Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India.
authors.forename: Amita
authors.initials: A
authors.lastname: Limaye
authors.affiliation: Diabetes Unit, KEM Hospital, Rasta Peth, Pune 411011, India.
authors.forename: Dattatray S
authors.initials: DS
authors.lastname: Bhat
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Januszewski
authors.affiliation: National Center for Cell Science, Ganeshkhind Road, Pune 411007, India.
authors.forename: Malati R
authors.initials: MR
authors.lastname: Umrani
authors.affiliation: Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Amaresh K
authors.initials: AK
authors.lastname: Ranjan
authors.affiliation: National Toxicology Center, 36/1/1 MN199, Vadgaon Khurd, Singhgad Road, Pune 411041, India.
authors.forename: Kishori
authors.initials: K
authors.lastname: Apte
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Pranav
authors.initials: P
authors.lastname: Yajnik
authors.affiliation: National Center for Cell Science, Ganeshkhind Road, Pune 411007, India; Manipal Institute of Regenerative Medicine, Manipal University, Bangalore, India.
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Bhonde
authors.affiliation: Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Galande
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Keech
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.affiliation: Diabetes Unit, KEM Hospital, Rasta Peth, Pune 411011, India.
authors.forename: Chittaranjan S
authors.initials: CS
authors.lastname: Yajnik
mesh_terms: D050154:Adiposity; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D004198:Disease Susceptibility; D006801:Humans; D044342:Malnutrition / Q000150:complications / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar