Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice.
OBJECTIVE
Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F(1)-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy.


METHODS
We intercrossed female and male F(1) adult control (C) and UN mice and characterized metabolic phenotypes in F(2) offspring.


RESULTS
We demonstrate that 1) reduced birth weight progresses to F(2) offspring through the paternal line (Cfemale -Cmale = 1.64 g; Cfemale -UNmale = 1.57 g, P < 0.05; UNfemale -Cmale = 1.64 g; UNfemale -UNmale = 1.60 g, P < 0.05), 2) obesity progresses through the maternal line (percent body fat: Cfemale -Cmale = 22.4%; Cfemale -UNmale = 22.9%; UNfemale -Cmale = 25.9%, P < 0.05; UNfemale -UNmale = 27.5%, P < 0.05), and 3) IGT progresses through both parental lineages (glucose tolerance test area under curve Cfemale -Cmale = 100; Cfemale -UNmale = 122, P < 0.05; UNfemale -Cmale = 131, P < 0.05; UNfemale -UNmale = 151, P < 0.05). Mechanistically, IGT in both F(1) and F(2) generations is linked to impaired beta-cell function, explained, in part, by dysregulation of Sur1 expression.


CONCLUSIONS
Maternal undernutrition during pregnancy (F(0)) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).
Jimenez-Chillaron
Josep C
JC
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
Isganaitis
Elvira
E
Charalambous
Marika
M
Gesta
Stephane
S
Pentinat-Pelegrin
Thais
T
Faucette
Ryan R
RR
Otis
Jessica P
JP
Chow
Alice
A
Diaz
Ruben
R
Ferguson-Smith
Anne
A
Patti
Mary-Elizabeth
ME
D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000502:physiology; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D044342:Malnutrition / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D039382:Maternal Nutritional Physiological Phenomena / Q000502:physiology; D008431:Maternal-Fetal Exchange / Q000502:physiology; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D013997:Time Factors