Size Does Matter: Litter Size Strongly Determines Adult Metabolism in Rodents
2020; Cell Press; Volume: 32; Issue: 3 Linguagem: Inglês
10.1016/j.cmet.2020.07.014
ISSN1932-7420
AutoresMarcela Parra-Vargas, Marta Ramón-Krauel, Carles Lerín, Josep C. Jiménez‐Chillarón,
Tópico(s)Diet and metabolism studies
ResumoIn this essay, we highlight how litter size in rodents is a strong determinant of neonatal growth and long-term metabolic health. Based on these effects, we strongly advise that scientific articles that utilize rodent models for obesity and metabolic research should include information on the litter sizes in the study to increase the data transparency of such reports. In this essay, we highlight how litter size in rodents is a strong determinant of neonatal growth and long-term metabolic health. Based on these effects, we strongly advise that scientific articles that utilize rodent models for obesity and metabolic research should include information on the litter sizes in the study to increase the data transparency of such reports. Infant growth trajectory is a major determinant of metabolic health later in life. In particular, rapid weight gain increases the risk of several chronic diseases during adulthood, including obesity, type 2 diabetes, cardiovascular disease, and several types of cancer. Reducing litter size in rodents fully recapitulates the human pathophysiology. Mice and rats reared in small litters (2–4 pups per female) show rapid neonatal weight gain, likely due to less feeding competition during nursing and late-onset metabolic dysfunction. Strikingly, this effect has been largely replicated in multiple strains of mice and rats, as well as in different experimental conditions, suggesting that early growth trajectory is a conserved adaptive response to offspring size. Given the importance of litter size in determining adult metabolism, we strongly advocate for reporting this information in articles describing animal models of obesity and metabolic disease. Epidemiological and clinical data indicate that early growth is a strong determinant of adult disease risk. Specifically, accelerated infant growth is associated with a higher risk of developing chronic non-communicable diseases, including obesity, type 2 diabetes, and cardiovascular disease (McGill, 1998McGill Jr., H.C. Nutrition in early life and cardiovascular disease.Curr. Opin. Lipidol. 1998; 9: 23-27Crossref PubMed Scopus (16) Google Scholar; Stettler et al., 2002Stettler N. Zemel B.S. Kumanyika S. Stallings V.A. Infant weight gain and childhood overweight status in a multicenter, cohort study.Pediatrics. 2002; 109: 194-199Crossref PubMed Scopus (527) Google Scholar; Gluckman et al., 2008Gluckman P.D. Hanson M.A. Cooper C. Thornburg K.L. Effect of in utero and early-life conditions on adult health and disease.N. Engl. J. Med. 2008; 359: 61-73Crossref PubMed Scopus (2359) Google Scholar; Leunissen et al., 2009Leunissen R.W. Kerkhof G.F. Stijnen T. Hokken-Koelega A. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood.JAMA. 2009; 301: 2234-2242Crossref PubMed Scopus (342) Google Scholar; Durmuş et al., 2010Durmuş B. Mook-Kanamori D.O. Holzhauer S. Hofman A. van der Beek E.M. Boehm G. Steegers E.A. Jaddoe V.W. Growth in foetal life and infancy is associated with abdominal adiposity at the age of 2 years: the generation R study.Clin. Endocrinol. (Oxf.). 2010; 72: 633-640Crossref PubMed Scopus (43) Google Scholar; Körner et al., 2019Körner A. Kiess W. Vogel M. Persistence of obesity from early childhood onward.N. Engl. J. Med. 2019; 380: 194-195PubMed Google Scholar). Rapid growth during infancy is primarily mediated by overfeeding and excessive calorie intake (Singhal et al., 2010Singhal A. Kennedy K. Lanigan J. Fewtrell M. Cole T.J. Stephenson T. Elias-Jones A. Weaver L.T. Ibhanesebhor S. MacDonald P.D. et al.Nutrition in infancy and long-term risk of obesity: evidence from 2 randomized controlled trials.Am. J. Clin. Nutr. 2010; 92: 1133-1144Crossref PubMed Scopus (142) Google Scholar). These observations in humans have been replicated in several experimental animal models. In rodents, accelerated neonatal growth can be induced by reducing the litter size at birth (for review, see Habbout et al., 2013Habbout A. Li N. Rochette L. Vergely C. Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences.J. Nutr. 2013; 143: 553-562Crossref PubMed Scopus (85) Google Scholar). Mice and rats raised in small litters exhibit neonatal overfeeding, leading to rapid weight gain and late-onset metabolic disorders. These include obesity, insulin resistance, impaired glucose tolerance, hepatic steatosis, and renal and cardiometabolic defects (extended list of publications is reported in Table 1), which together affect lifespan (Preston et al., 2018Preston J.D. Reynolds L.J. Pearson K.J. Developmental origins of health span and life span: a mini-review.Gerontology. 2018; 64: 237-245Crossref PubMed Scopus (21) Google Scholar; Miller et al., 2002Miller R.A. Harper J.M. Galecki A. Burke D.T. Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice.Aging Cell. 2002; 1: 22-29Crossref PubMed Scopus (158) Google Scholar; Ozanne and Hales, 2004Ozanne S.E. Hales C.N. Lifespan: catch-up growth and obesity in male mice.Nature. 2004; 427: 411-412Crossref PubMed Scopus (436) Google Scholar). These long-term metabolic derangements can be due to alterations in either the central nervous system typically leading to hyperphagia (Plagemann et al., 2009Plagemann A. Harder T. Brunn M. Harder A. Roepke K. Wittrock-Staar M. Ziska T. Schellong K. Rodekamp E. Melchior K. Dudenhausen J.W. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome.J. Physiol. 2009; 587: 4963-4976Crossref PubMed Scopus (313) Google Scholar; Plagemann, 2006Plagemann A. Perinatal nutrition and hormone-dependent programming of food intake.Horm. Res. 2006; 65: 83-89Crossref PubMed Scopus (152) Google Scholar; Li et al., 2013Li G. Kohorst J.J. Zhang W. Laritsky E. Kunde-Ramamoorthy G. Baker M.S. Fiorotto M.L. Waterland R.A. Early postnatal nutrition determines adult physical activity and energy expenditure in female mice.Diabetes. 2013; 62: 2773-2783Crossref PubMed Scopus (36) Google Scholar; Collden et al., 2014Collden G. Balland E. Parkash J. Caron E. Langlet F. Prevot V. Bouret S.G. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin.Mol. Metab. 2014; 4: 15-24Crossref PubMed Scopus (82) Google Scholar; Zhu et al., 2016Zhu S. Eclarinal J. Baker M.S. Li G. Waterland R.A. Developmental programming of energy balance regulation: is physical activity more 'programmable' than food intake?.Proc. Nutr. Soc. 2016; 75: 73-77Crossref PubMed Scopus (12) Google Scholar) or in peripheral tissues (Glavas et al., 2010Glavas M.M. Kirigiti M.A. Xiao X.Q. Enriori P.J. Fisher S.K. Evans A.E. Grayson B.E. Cowley M.A. Smith M.S. Grove K.L. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet.Endocrinology. 2010; 151: 1598-1610Crossref PubMed Scopus (116) Google Scholar; Bei et al., 2015Bei F. Jia J. Jia Y.Q. Sun J.H. Liang F. Yu Z.Y. Cai W. Long-term effect of early postnatal overnutrition on insulin resistance and serum fatty acid profiles in male rats.Lipids Health Dis. 2015; 14: 96Crossref PubMed Scopus (23) Google Scholar; Conceição et al., 2013Conceição E.P. Franco J.G. Oliveira E. Resende A.C. Amaral T.A. Peixoto-Silva N. Passos M.C. Moura E.G. Lisboa P.C. Oxidative stress programming in a rat model of postnatal early overnutrition--role of insulin resistance.J. Nutr. Biochem. 2013; 24: 81-87Crossref PubMed Scopus (39) Google Scholar; Du et al., 2015Du Q. Hosoda H. Umekawa T. Kinouchi T. Ito N. Miyazato M. Kangawa K. Ikeda T. Postnatal weight gain induced by overfeeding pups and maternal high-fat diet during the lactation period modulates glucose metabolism and the production of pancreatic and gastrointestinal peptides.Peptides. 2015; 70: 23-31Crossref PubMed Scopus (21) Google Scholar; Ramon-Krauel et al., 2018Ramon-Krauel M. Pentinat T. Bloks V.W. Cebrià J. Ribo S. Pérez-Wienese R. Vilà M. Palacios-Marin I. Fernández-Pérez A. Vallejo M. et al.Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.FASEB J. 2018; (Published online May 29, 2018)https://doi.org/10.1096/fj.201700717RRCrossref PubMed Scopus (11) Google Scholar).Table 1Summary of Phenotypic Outcomes in Rodents Reared in Small and Large LittersStrainSexLitter Size (Pup Number)Adult Metabolic PhenotypeReferencesBWFat MassOther Long-Term Metabolic Effects Associated with Litter SizeMiceICRMC8Pentinat et al., 2010Pentinat T. Ramon-Krauel M. Cebria J. Diaz R. Jimenez-Chillaron J.C. Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition.Endocrinology. 2010; 151: 5617-5623Crossref PubMed Scopus (105) Google Scholar; Ramon-Krauel et al., 2018Ramon-Krauel M. Pentinat T. Bloks V.W. Cebrià J. Ribo S. Pérez-Wienese R. Vilà M. Palacios-Marin I. Fernández-Pérez A. Vallejo M. et al.Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.FASEB J. 2018; (Published online May 29, 2018)https://doi.org/10.1096/fj.201700717RRCrossref PubMed Scopus (11) Google ScholarSL4↑↑Insulin resistance, glucose intolerance, hypertriglyceridemia, hyperinsulinemia, hepatic steatosis, and hepatic insulin resistanceLL12↓↓Lower insulinemia, improved hepatic insulin sensitivity, and reduced hepatic diacylglycerol and triacylglycerol levelsC57BL/6MC10Habbout et al., 2013Habbout A. Li N. Rochette L. Vergely C. Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences.J. Nutr. 2013; 143: 553-562Crossref PubMed Scopus (85) Google ScholarSL3↑↑Hyperinsulinemia, increased plasma cholesterol and leptin levels, and alterations in cardiometabolic and oxidative parametersC57BL/6MC9Li et al., 2016Li N. Guenancia C. Rigal E. Hachet O. Chollet P. Desmoulins L. Leloup C. Rochette L. Vergely C. Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice.Sci. Rep. 2016; 6: 30817Crossref PubMed Scopus (17) Google ScholarSL3Insulin resistance, glucose intolerance, hyperinsulinemia, and hyperleptinemiaSwissF, MC9Aubert et al., 1980Aubert R. Suquet J.P. Lemonnier D. Long-term morphological and metabolic effects of early under- and over-nutrition in mice.J. Nutr. 1980; 110: 649-661Crossref PubMed Scopus (67) Google ScholarSL4↑↑Enlarged and more numerous adipocytes, hyperinsulinemia, increased total lipid synthesis in liver. No glucose intolerance.LL20↓↓Smaller and less numerous adipocytes, decreased serum insulin and total insulin pancreas levels, reduced free cholesterol synthesis in liver, and decreased conversion of glucose into triglyceride-glycerol in adipose tissueSwissMC9Martins et al., 2008Martins M.R. Vieira A.K. de Souza E.P. Moura A.S. Early overnutrition impairs insulin signaling in the heart of adult Swiss mice.J. Endocrinol. 2008; 198: 591-598Crossref PubMed Scopus (18) Google ScholarSL3↑↑Glucose intolerance, hyperinsulinemia, increased insulin/glucose ratio, and impaired cardiac insulin signalingSwiss WebsterMC10Glavas et al., 2010Glavas M.M. Kirigiti M.A. Xiao X.Q. Enriori P.J. Fisher S.K. Evans A.E. Grayson B.E. Cowley M.A. Smith M.S. Grove K.L. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet.Endocrinology. 2010; 151: 1598-1610Crossref PubMed Scopus (116) Google ScholarSL3↑↑Leptin resistance in the arcuate nucleus. In response to high-fat diet: insulin resistance and severe hepatic steatosis.Hybrid: C57BL/6J and 129/SvPasF, MC6Kappeler et al., 2009Kappeler L. De Magalhaes Filho C. Leneuve P. Xu J. Brunel N. Chatziantoniou C. Le Bouc Y. Holzenberger M. Early postnatal nutrition determines somatotropic function in mice.Endocrinology. 2009; 150: 314-323Crossref PubMed Scopus (64) Google ScholarSL3↑NDInsulin resistance, glucose intolerance, hyperinsulinemia, hyperleptinemia, and increased HDL, cholesterol, total colesterol, and triglyceride plasma levelsLL10↓NDGlucose intolerance and decreased leptin, HDL, and total cholesterolICRMC10Ye et al., 2012Ye Z. Huang Y. Liu D. Chen X. Wang D. Huang D. Zhao L. Xiao X. Obesity induced by neonatal overfeeding worsens airway hyperresponsiveness and inflammation.PLoS One. 2012; 7: e47013Crossref PubMed Scopus (17) Google ScholarSL3↑NDGlucose intolerance and hyperleptinemiaFVB/NJF, MC9Li et al., 2013Li G. Kohorst J.J. Zhang W. Laritsky E. Kunde-Ramamoorthy G. Baker M.S. Fiorotto M.L. Waterland R.A. Early postnatal nutrition determines adult physical activity and energy expenditure in female mice.Diabetes. 2013; 62: 2773-2783Crossref PubMed Scopus (36) Google Scholar; Zhu et al., 2016Zhu S. Eclarinal J. Baker M.S. Li G. Waterland R.A. Developmental programming of energy balance regulation: is physical activity more 'programmable' than food intake?.Proc. Nutr. Soc. 2016; 75: 73-77Crossref PubMed Scopus (12) Google ScholarSL4↑↑Reduced energy expenditure and physical activity in femalesFVBFC8Caron et al., 2012Caron E. Ciofi P. Prevot V. Bouret S.G. Alteration in neonatal nutrition causes perturbations in hypothalamic neural circuits controlling reproductive function.J. Neurosci. 2012; 32: 11486-11494Crossref PubMed Scopus (69) Google ScholarSL3↑NDDeleterious effects on neuronal projections from the arcuate nucleus, the preoptic region involved in the control of reproductionLL15↓NDDelayed puberty and defective development of axonal projections from the arcuate nucleus to the preoptic regionC57BL/6MC9Yzydorczyk et al., 2019Yzydorczyk C. Li N. Rigal E. Chehade H. Mosig D. Armengaud J.B. Rolle T. Krishnasamy A. Orozco E. Siddeek B. et al.Calorie restriction in adulthood reduces hepatic disorders induced by transient postnatal overfeeding in mice.Nutrients. 2019; 11: E2796Crossref PubMed Scopus (6) Google ScholarSL3NDNDHepatic steatosis (micro-steatosis, fibrosis associated with oxidative stress)C57BL/6MC7Collden et al., 2014Collden G. Balland E. Parkash J. Caron E. Langlet F. Prevot V. Bouret S.G. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin.Mol. Metab. 2014; 4: 15-24Crossref PubMed Scopus (82) Google ScholarSL3↑↑Hyperphagia, hyperglycemia, and central resistance to peripheral ghrelinRatsSprague-DawleyMC10Dai et al., 2018Dai Y. Zhou N. Yang F. Zhou S. Sha L. Wang J. Li X. Effects of postnatal overfeeding and fish oil diet on energy expenditure in rats.Pediatr. Res. 2018; 83: 156-163Crossref PubMed Scopus (5) Google ScholarSL3↑↑Glucose intolerance, dyslipidemia, reduced O2 consumption, and heat productionSprague-DawleyMC10Hou et al., 2011Hou M. Liu Y. Zhu L. Sun B. Guo M. Burén J. Li X. Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats.PLoS ONE. 2011; 6: e25726Crossref PubMed Scopus (32) Google ScholarSL3↑↑Hyperinsulinemia, increased insulin/glucose ratio, hyperleptinemia, elevated corticosterone, and altered glucocorticoid metabolismWistarMC10Cunha et al., 2009Cunha A.C. Pereira R.O. Pereira M.J. Soares Vde.M. Martins M.R. Teixeira M.T. Souza E.P. Moura A.S. Long-term effects of overfeeding during lactation on insulin secretion--the role of GLUT-2.J. Nutr. Biochem. 2009; 20: 435-442Crossref PubMed Scopus (44) Google ScholarSL3↑↑Hyperinsulinemia, hyperleptinemia, hyperphagia, impaired glucose tolerance at 30 min following glucose infusion, and increased glucose-stimulated insulin secretion by pancreatic isletsWistarMC10Boullu-Ciocca et al., 2005Boullu-Ciocca S. Dutour A. Guillaume V. Achard V. Oliver C. Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome.Diabetes. 2005; 54: 197-203Crossref PubMed Scopus (153) Google ScholarSL3↑↑Glucose intolerance, hyperphagia, hyperglycemia, hyperinsulinemia, hyperleptinemia, elevated plasma free fatty acid levels, increased adipose tissue glucocorticoid sensitivity, and permanent upregulation of the hypothalamus-pituitary-adrenal axisWistarMC10Conceição et al., 2013Conceição E.P. Franco J.G. Oliveira E. Resende A.C. Amaral T.A. Peixoto-Silva N. Passos M.C. Moura E.G. Lisboa P.C. Oxidative stress programming in a rat model of postnatal early overnutrition--role of insulin resistance.J. Nutr. Biochem. 2013; 24: 81-87Crossref PubMed Scopus (39) Google Scholar; Rodrigues et al., 2011Rodrigues A.L. de Moura E.G. Passos M.C. Trevenzoli I.H. da Conceição E.P. Bonono I.T. Neto J.F. Lisboa P.C. Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats.J. Nutr. Biochem. 2011; 22: 109-117Crossref PubMed Scopus (55) Google ScholarSL3↑↑Hyperphagia, hepatic steatosis (micro-steatosis), lipid oxidative damage, impaired hepatic insulin signaling, central leptin resistance, and reduced plasma HDL cholesterol. No glucose intolerance.WistarMC10Rodrigues et al., 2007Rodrigues A.L. De Souza E.P. Da Silva S.V. Rodrigues D.S. Nascimento A.B. Barja-Fidalgo C. De Freitas M.S. Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition.J. Endocrinol. 2007; 195: 485-494Crossref PubMed Scopus (41) Google ScholarSL4↑↑Hyperphagia, decreased insulin-induced glucose uptake into isolated adipocytes, and impaired insulin signaling in isolated adipocytesSprague-DawleyMC10Mozeš et al., 2013Mozeš Š. Šefcíková Z. Bujnáková D. Racek L. Effect of antibiotic treatment on intestinal microbial and enzymatic development in postnatally overfed obese rats.Obesity (Silver Spring). 2013; 21: 1635-1642Crossref PubMed Scopus (10) Google ScholarSL4↑↑Gut microbiota composition is altered in young SL ratsWistarF, MC12Clarke et al., 2012Clarke M.A. Stefanidis A. Spencer S.J. Postnatal overfeeding leads to obesity and exacerbated febrile responses to lipopolysaccharide throughout life.J. Neuroendocrinol. 2012; 24: 511-524Crossref PubMed Scopus (47) Google ScholarSL4↑↑Exacerbated inflammatory responses to lipopolysaccharide, enhanced expression of Toll-like receptors 2/4 in adipose tissue, and upregulated downstream pro-inflammatory cascadeWistarF, MC12Sánchez-Garrido et al., 2013Sánchez-Garrido M.A. Castellano J.M. Ruiz-Pino F. Garcia-Galiano D. Manfredi-Lozano M. Leon S. Romero-Ruiz A. Diéguez C. Pinilla L. Tena-Sempere M. Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges.Endocrinology. 2013; 154: 3387-3400Crossref PubMed Scopus (65) Google Scholar; Castellano et al., 2011Castellano J.M. Bentsen A.H. Sánchez-Garrido M.A. Ruiz-Pino F. Romero M. Garcia-Galiano D. Aguilar E. Pinilla L. Diéguez C. Mikkelsen J.D. Tena-Sempere M. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system.Endocrinology. 2011; 152: 3396-3408Crossref PubMed Scopus (138) Google ScholarSL4↑NDEarly puberty. In females: hyperinsulinemia and hyperleptinemia.LL20↓NDDelayed puberty. In females: hypoleptinemia.WistarMC12Habbout et al., 2012Habbout A. Delemasure S. Goirand F. Guilland J.C. Chabod F. Sediki M. Rochette L. Vergely C. Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood.Biochimie. 2012; 94: 117-124Crossref PubMed Scopus (32) Google ScholarSL3↑NDHyperinsulinemia, hyperglycemia, hyperleptinemia, hyperphagia, reduced adiponectin levels, and increased circulating oxidative stressWistarMC10Davidowa and Plagemann, 2007Davidowa H. Plagemann A. Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats.Neuroreport. 2007; 18: 521-524Crossref PubMed Scopus (62) Google ScholarSL3↑NDInsulin resistance of hypothalamic arcuate neuronsWistarMC12Wiedmer et al., 2002Wiedmer P. Klaus S. Ortmann S. Energy metabolism of young rats after early postnatal overnutrition.Br. J. Nutr. 2002; 88: 301-306Crossref PubMed Scopus (19) Google ScholarSL2↑↑Early increased total energy expenditure with no effects on energy metabolism at weeks 8 to 12Sprague-DawleyF, MC10Boubred et al., 2009Boubred F. Daniel L. Buffat C. Feuerstein J.M. Tsimaratos M. Oliver C. Dignat-George F. Lelièvre-Pégorier M. Simeoni U. Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats.Am. J. Physiol. Renal Physiol. 2009; 297: F943-F951Crossref PubMed Scopus (67) Google Scholar, Buffat et al., 2007Buffat C. Boubred F. Mondon F. Chelbi S.T. Feuerstein J.M. Lelièvre-Pégorier M. Vaiman D. Simeoni U. Kidney gene expression analysis in a rat model of intrauterine growth restriction reveals massive alterations of coagulation genes.Endocrinology. 2007; 148: 5549-5557Crossref PubMed Scopus (37) Google ScholarSL3↑↑In males: elevated blood pressure, glomerulosclerosis, and chronic kidney diseaseSprague-DawleyMC10Yim et al., 2013Yim H.E. Ha K.S. Bae I.S. Yoo K.H. Hong Y.S. Lee J.W. Overweight, hypertension and renal dysfunction in adulthood of neonatally overfed rats.J. Nutr. Biochem. 2013; 24: 1324-1333Crossref PubMed Scopus (14) Google ScholarSL3↑NDElevated blood pressure and renal dysfunctionSprague-DawleyMC12Velkoska et al., 2008Velkoska E. Cole T.J. Dean R.G. Burrell L.M. Morris M.J. Early undernutrition leads to long-lasting reductions in body weight and adiposity whereas increased intake increases cardiac fibrosis in male rats.J. Nutr. 2008; 138: 1622-1627Crossref PubMed Scopus (48) Google ScholarSL3↑∗=Hyperleptinemia and cardiac fibrosisLL18↓↓Reduced organ weights (liver, kidney, and white adipose tissue)WistarF, MC10Costa et al., 2019Costa V.M.G. Andreazzi A.E. Bolotari M. Lade C.G. Guerra M.O. Peters V.M. Effect of postnatal overfeeding on the male and female Wistar rat reproductive parameters.J. Dev. Orig. Health Dis. 2019; 10: 667-675Crossref PubMed Scopus (4) Google ScholarSL4↑↑Glucose intolerance and hyperphagia. In males: insulin resistance. In females: delayed puberty.∗Heavier at 16 weeks of age, but the difference did not reach statistical significance. ↑: increased compared to control. ↓: reduced compared to control. =: similar to control. HDL, high-density lipoprotein; C, control; SL, small litter; LL, large litter; BW, body weight; F, female; M, male; ND, not determined. Open table in a new tab ∗Heavier at 16 weeks of age, but the difference did not reach statistical significance. ↑: increased compared to control. ↓: reduced compared to control. =: similar to control. HDL, high-density lipoprotein; C, control; SL, small litter; LL, large litter; BW, body weight; F, female; M, male; ND, not determined. Despite lab-to-lab differences, high variability in experimental design, and the large variety of species and strains being used, phenotypic outcomes are fairly similar in all the above-listed studies (Table 1). For example, litter size reduction has been conducted in rats (Sprague-Dawley and Wistar) and mice (Swiss, ICR-CD1, C57BL/6, FVB, and 129) with comparable results. Furthermore, the number of pups included in control (C) and small litter (SL) groups differs enormously depending on the study. Litter size was culled to 2, 3, or 4 pups per female in the SL group, whereas control females nursed between 6 and 12 pups during lactation. These differences have led to a large number of conditions in which the C:SL ratio significantly varied from 12C:4SL to 10C:3SL, 9C:4SL, 8C:4SL, or 6C:3SL, among many other combinations. Despite these differences, nearly all SL-raised rodents developed metabolic derangements during adulthood, with overweight and increased adiposity reported in 100% and 94% of the studies listed in Table 1, respectively. It is well known that strain-to-strain differences are partly attributed to genetic factors that influence physiologic outcomes, including energy expenditure and physical activity. Notably, despite the robust response imposed by litter size, the final array of metabolic phenotypes depends on the interaction between environment (litter size and growth) and genetics (species and strains). For example, we reported that litter size reduction in CD1 mice (8C:4SL) leads to adult obesity, insulin resistance, fatty liver, and glucose intolerance (Pentinat et al., 2010Pentinat T. Ramon-Krauel M. Cebria J. Diaz R. Jimenez-Chillaron J.C. Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition.Endocrinology. 2010; 151: 5617-5623Crossref PubMed Scopus (105) Google Scholar; Ramon-Krauel et al., 2018Ramon-Krauel M. Pentinat T. Bloks V.W. Cebrià J. Ribo S. Pérez-Wienese R. Vilà M. Palacios-Marin I. Fernández-Pérez A. Vallejo M. et al.Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.FASEB J. 2018; (Published online May 29, 2018)https://doi.org/10.1096/fj.201700717RRCrossref PubMed Scopus (11) Google Scholar). However, this same protocol in C57BL/6J mice leads to obesity and insulin resistance but fails to induce glucose intolerance or fatty liver (unpublished data). Together, these data suggest that litter size in rodents is a strong independent determinant of adult metabolic health, which is tuned by the genetic background. However, this statement is solely based on data from SL and control offspring. The next question then is whether offspring size influences adult metabolism in small-to-medium-to-large litters. This was elegantly answered by Zhang and colleagues in a study in which 3, 4, 5, 6, 7, 8, 9, or 10 pups were maintained per female during lactation (Zhang et al., 2012Zhang L.N. Morgan D.G. Clapham J.C. Speakman J.R. Factors predicting nongenetic variability in body weight gain induced by a high-fat diet in inbred C57BL/6J mice.Obesity (Silver Spring). 2012; 20: 1179-1188Crossref PubMed Scopus (22) Google Scholar). Strikingly, litter size showed a strong inverse correlation with body weight at weaning and fat mass at 9 weeks of age. To the best of our knowledge, this is the most accurate study reporting the compelling effect of litter size on body weight and fat mass across the offspring size continuum. In agreement with the previous study, rearing pups in large litters (LL) induces the opposite effect of the SL size paradigm (Table 1) (Ramon-Krauel et al., 2018Ramon-Krauel M. Pentinat T. Bloks V.W. Cebrià J. Ribo S. Pérez-Wienese R. Vilà M. Palacios-Marin I. Fernández-Pérez A. Vallejo M. et al.Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.FASEB J. 2018; (Published online May 29, 2018)https://doi.org/10.1096/fj.201700717RRCrossref PubMed Scopus (11) Google Scholar; Kappeler et al., 2009Kappeler L. De Magalhaes Filho C. Leneuve P. Xu J. Brunel N. Chatziantoniou C. Le Bouc Y. Holzenberger M. Early postnatal nutrition determines somatotropic function in mice.Endocrinology. 2009; 150: 314-323Crossref PubMed Scopus (64) Google Scholar; Caron et al., 2012Caron E. Ciofi P. Prevot V. Bouret S.G. Alteration in neonatal nutrition causes perturbations in hypothalamic neural circuits controlling reproductive function.J. Neurosci. 2012; 32: 11486-11494Crossref PubMed Scopus (69) Google Scholar; Aubert et al., 1980Aubert R. Suquet J.P. Lemonnier D. Long-term morphological and metabolic effects of early under- and over-nutrition in mice.J. Nutr. 1980; 110: 649-661Crossref PubMed Scopus (67) Google Scholar; Plagemann et al., 1999Plagemann A. Harder T. Rake A. Waas T. Melchior K. Ziska T. Rohde W. Dörner G. Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats.J. Neuroendocrinol. 1999; 11: 541-546Crossref PubMed Scopus (173) Google Scholar; Sánchez-Garrido et al., 2013Sánchez-Garrido M.A. Castellano J.M. Ruiz-Pino F. Garcia-Galiano D. Manfredi-Lozano M. Leon S. Romero-Ruiz A. Diéguez C. Pinilla L. Tena-Sempere M. Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges.Endocrinology. 2013; 154: 3387-3400Crossref PubMed Scopus (65) Google Scholar; Castellano et al., 2011Castellano J.M. Bentsen A.H. Sánchez-Garrido M.A. Ruiz-Pino F. Romero M. Garcia-Galiano D. Aguilar E. Pinilla L. Diéguez C. Mikkelsen J.D. Tena-Sempere M. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system.Endocrinology. 2011; 152: 3396-3408Crossref PubMed Scopus (138) Google Scholar). LL-raised rodents show slower growth rate during lactation than controls. Furthermore, adult LL-raised mice and rats are leaner and have lower body weight. Litter size enlargement also extends median and maximal lifespan in mice (Sun et al., 2009Sun L. Sadighi Akha A.A. Miller R.A. Harper J.M. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age.J. Gerontol. A Biol. Sci. Med. Sci. 2009; 64: 711-722Crossref PubMed Scopus (181) Google Scholar; Sadagurski et al., 2014Sadagurski M. Landeryou T. Blandino-Rosano M. Cady G. Elghazi L. Meister D. See L. Bartke A. Bernal-Mizrachi E. Miller R.A. Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis.Am. J. Physiol. Endocrinol. Metab. 2014; 306: E1305-E1314Crossref PubMed Scopus (25) Google Scholar). These results are reproducible regardless of the species, strain, sex, and C:LL ratios used (8C:12LL, 8C:15LL, 9C:20LL, 12C:18LL, and 12C:20LL). While fairly robust across studies, other metabolic effects, including insulin sensitivity of hepatic TAG content, tend to be subtle and dissipate with aging. Hence, although availa
Referência(s)