OR18-6 Metabolic plasticity and energy/nutrient sensing distortion in mice exposed to gestational undernutrition

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR18-Diabetes-Associated Genes & Pathways
Basic/Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 304 (Moscone Center)
Aristides Lytras*1, Elvira Isganaitis2, Yusuke Adachi3, Michael Chen2, Wen Kong3, Aparna Sharma3, Huijuan Ma3, Vicencia Sales3, Alison Burkart3, George P. Chrousos1 and Mary Elizabeth Patti4
1Biomedical Research Foundation, Academy of Athens, Athens, Greece, 2Joslin Diabetes Center, Boston, MA, 3Joslin Diabetes Center, 4Joslin Diab Ctr/Harvard Med, Boston, MA
Early adiposity is a typical feature of the low birth weight phenotype associated with mouse gestational undernutrition (UN; attained by 50% reduction of food supply, from day 12.5 to 18.5 of pregnancy). We hypothesize that energy/nutrient sensing (e/Ns) distortion (i.e. the disruption of tissue-specific and whole body energy/nutrient sensing mechanisms) in this setting can result in altered fuel partitioning and relative tissue growth. To assess this hypothesis, we analysed morphometric and molecular data, and observed an inverse relation between liver weight (LW) and epididymal fat weight (EFW) in UN (n=13, r=0.789, p<0.002), but not in control (C; n=16) adult male mice (10 weeks; rC vs. rUN: p<0.02). We then asked whether the birth weight (signifying the extent of the success of an UN fetus to overcome adversity and achieve growth) may be associated with these patterns. First, we observed an inverted U-shape pattern for the correlation of birth weight with adult weight in the full C/UN cohort. Moreover, in UN mice, we observed a striking U-shaped relationship between birth weight and %LW (LW expressed as % of body weight), and an inverse U-shaped relationship for birth weight vs. %EFW. We next examined key components of the hepatic AMPK/mTOR energy/nutrient sensor system as potential contributors to altered body composition. Among these candidates, ULK1 is a competitive target of mTOR and AMPK kinase activities and regulates autophagy (1). Phosphorylation of ULK1 (p-ULK1Ser757), correlated significantly and inversely with body weight (n=26, r= -0.511, p<0.008), LW (r= -0.66, p<0.0003), %LW (r= -0.593, p<0.002), and the LW/EFW ratio (r=-0.646, p<0.0004). A positive correlation was observed between hepatic p-ULK1 and %EFW (r= 0.434, p<0.03). Furthermore an inverted U-shape pattern depicted the correlation between birth weight and adult hepatic p-ULK1 in UN mice. UN animals present with reduced hepatic levels of the scaffolding subunit of protein phosphatase 2A (PP2A; inhibitor of various AMPK/mTOR components) (2), and genome-wide DNA methylation analysis of UN hepatic tissue, at 3 weeks of age, identified differentially methylated CpG islands in the vicinity of genes encoding for various PP2A subunits (unpublished observations). We thus hypothesize that in order to maximize survival in response to severe UN, the e/N sensor system may be reset, possibly through epigenetic mechanisms and relevant developmental metabolic plasticity. The impact of such mechanisms may be reflected in the correlation patterns linking birth weight with the postnatal hepatic expression and phosphorylation of key elements of the e/N sensor system, as observed in our cohort. Together, these effects may contribute to differential tissue expansion and relative tissue mass, reflecting differential energy/fuel partitioning and dysmetabolism when nutrient supply is ample during adult life.

(1) Kim J et al., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011; 13:132-41 (2) Lytras et al., Altered Levels of Components of the AMPK/mTOR Sensor System in the Gestational Undernutrition - Low Birth Weight (UN-LBW) Mouse Model of Adiposity.  

American Diabetes Association 72nd Scientific Sessions 2012, Abstract #

2800-PO

Nothing to Disclose: AL, EI, YA, MC, WK, AS, HM, VS, AB, GPC, MEP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by a Marie Curie International Outgoing Fellowship of the European Commission (FP7 MC-IOF-2009 253131) to Aristides Lytras.
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