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Metabolic imprinting due to small litter size mitigates insulin resistance through the interscapular brown adipose tissue activation in a high-sucrose diet model

Published online by Cambridge University Press:  04 August 2025

Isabela Jesus de Deus Open the ORCID record for Isabela Jesus de Deus [Opens in a new window] ,
Aline Rezende Ribeiro de Abreu Open the ORCID record for Aline Rezende Ribeiro de Abreu [Opens in a new window] ,
Miliane Martins de Andrade Fagundes Open the ORCID record for Miliane Martins de Andrade Fagundes [Opens in a new window] ,
Juliana Letícia Silva Open the ORCID record for Juliana Letícia Silva [Opens in a new window] ,
Gustavo Silveira Breguez Open the ORCID record for Gustavo Silveira Breguez [Opens in a new window] ,
Ângela Antunes Silva ,
Érika Cristina da Silva Oliveira Siqueira ,
Cláudia Martins Carneiro Open the ORCID record for Cláudia Martins Carneiro [Opens in a new window] ,
Daniela Caldeira Costa Open the ORCID record for Daniela Caldeira Costa [Opens in a new window]  and
Sílvia Paula-Gomes Open the ORCID record for Sílvia Paula-Gomes [Opens in a new window]
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Isabela Jesus de Deus
Affiliation:
Laboratory of Experimental Nutrition, Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil Postgraduate Program in Health and Nutrition, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Aline Rezende Ribeiro de Abreu
Affiliation:
Laboratory of Experimental Nutrition, Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil Postgraduate Program in Health and Nutrition, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Miliane Martins de Andrade Fagundes
Affiliation:
Laboratory of Experimental Nutrition, Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil Postgraduate Program in Health and Nutrition, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Juliana Letícia Silva
Affiliation:
Laboratory of Experimental Nutrition, Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil Postgraduate Program in Health and Nutrition, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Gustavo Silveira Breguez
Affiliation:
Multiuser Research Laboratory in Nutritional Biochemistry and Molecular Biology, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Ângela Antunes Silva
Affiliation:
Animal Science Center, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Érika Cristina da Silva Oliveira Siqueira
Affiliation:
Animal Science Center, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Cláudia Martins Carneiro
Affiliation:
Laboratory of Immunopathology, Research Center in Biological Sciences/NUPEB, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Daniela Caldeira Costa
Affiliation:
Laboratory of Metabolic Biochemistry, Department of Biological Sciences (DECBI), Institute of Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Sílvia Paula-Gomes
Affiliation:
Laboratory of Biochemistry and Molecular Biology, Department of Biological Sciences (DECBI), Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
Karina Barbosa de Queiroz*
Affiliation:
Laboratory of Experimental Nutrition, Department of Food, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil Postgraduate Program in Health and Nutrition, School of Nutrition, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
*
Corresponding author: Karina Barbosa de Queiroz; Email: karina.queiroz@ufop.edu.br
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Abstract

Metabolic imprinting refers to lasting metabolic changes from early-life environmental exposures, especially nutritional, that impact adult health and chronic disease risk. We investigated whether metabolic imprinting by small litter size (SL) activates interscapular brown adipose tissue (iBAT) and affects glucose and lipid metabolism, oxidative damage, and insulin resistance (IR) in young rats exposed to a high-sucrose diet (HSD) over eight weeks. Male Wistar rats (n = 48) were assigned to control (eight pups/ dam; CL) and small litter (four pups/ dam; SL) groups. Post-weaning (21 days), they were divided into four dietary groups: (i) standard diet (STD, chow diet) from CL, or (ii) SL; (iii) HSD (30% sucrose) from CL, or (iv) SL, for eight weeks. Afterward, animals were euthanized for analysis of iBAT and serum samples. HSD caused hypertrophy, IR, and oxidative damage in iBAT. However, the SL model attenuated HSD-induced IR by up-regulating p-AKT (Ser 473) and activating iBAT thermogenesis, resulting in decreased PGC1-α expression and up-regulating UCP1 expression, which contributed to iBAT hyperplasia. Additionally, SL reduced PKA activation and free fatty acid (FFA) release, decreasing the lipid oxidative damage observed in HSD-fed iBAT. These findings suggest that SL-induced metabolic imprinting enhances iBAT thermogenesis through p-AKT (Ser 473) and PGC1-α signaling, increases UCP1 expression, and reduces PKA substrates phosphorylation, decreasing FFA levels and oxidative damage following HSD exposure. While our results challenge the existing literature, we propose that the metabolic plasticity from the SL model allows rats to adapt to dietary variations and may protect against HSD-induced IR in adulthood.

Keywords

Metabolic imprintinglitter size effectinsulin resistanceiBAT activationUCP1

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Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 16 , 2025 , e29
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© The Author(s), 2025. Published by Cambridge University Press in association with The International Society for Developmental Origins of Health and Disease (DOHaD)

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References

Levin, BE. Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471), 1107–1121.CrossRefGoogle ScholarPubMed
Bonet, ML, Ribot, J, Sánchez, J, et al. Early life programming of adipose tissue remodeling and browning capacity by micronutrients and bioactive compounds as a potential anti-obesity strategy. Cells. 2024; 13(10), 870.CrossRefGoogle ScholarPubMed
Waterland, RA, Garza, C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 1999; 69(2), 179–197.CrossRefGoogle ScholarPubMed
Oben, JA, Mouralidarane, A, Samuelsson, AM, et al. Maternal obesity during pregnancy and lactation programs the development of offspring with non-alcoholic fatty liver disease in mice. J Hepatol. 2020; 52(6), 913–920.10.1016/j.jhep.2009.12.042CrossRefGoogle Scholar
Jiménez-Chillarón, JC, Díaz, R, Martínez, D, et al. The role of nutrition on epigenetic modifications and their implications on health. Biochimie. 2012; 94(11), 2242–2263.CrossRefGoogle ScholarPubMed
Semple, BD, Blomgren, K, Gimlin, K, Ferriero, DM, Noble-Haeusslein, LJ. Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013; 106, 1–16.10.1016/j.pneurobio.2013.04.001CrossRefGoogle ScholarPubMed
Sengupta, P. The laboratory rat: relating its age with human’s. Int J Prev Med. 2013; 4(6), 624–630.Google ScholarPubMed
Penkler, M, Hanson, M, Biesma, R, Müller, R. DOHaD in science and society: emergent opportunities and novel responsibilities. Philos Trans R Soc Lond B Biol Sci. 2019; 10(3), 268–273.Google ScholarPubMed
Lettieri-Barbato, D. Redox control of non-shivering thermogenesis. Mol Metab. 2019; 25, 11–19.CrossRefGoogle ScholarPubMed
Schnaider, JM, Borges, BE. Brown adipose tissue in adults as a study target in the development of new therapies for the management and treatment of obesity: an integrative review. J Med. 2021; 100, 460–471.Google Scholar
Huo, C, Song, Z, Yin, J, et al. Effect of acute cold exposure on energy metabolism and activity of brown adipose tissue in humans: a systematic review and meta-analysis. Front Physiol. 2022; 13, 917084.CrossRefGoogle Scholar
Saito, M, Matsushita, M, Yoneshiro, T, Okamatsu-Ogura, Y. Brown adipose tissue, diet-induced thermogenesis, and thermogenic food ingredients: from mice to men. Front Endocrinol. 2020; 11, 222.10.3389/fendo.2020.00222CrossRefGoogle Scholar
Spencer, SJ. Early life programming of obesity: the impact of the perinatal environment on the development of obesity and metabolic dysfunction in the offspring. Curr Diab Rev. 2012; 8(1), 55–68.CrossRefGoogle ScholarPubMed
Habbout, 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(5), 553–562.10.3945/jn.112.172825CrossRefGoogle Scholar
Xiao, XQ, Williams, SM, Grayson, BE, et al. Excess weight gain during the early postnatal period is associated with permanent reprogramming of brown adipose tissue adaptive thermogenesis. Endocrinology. 2007; 148(9), 4150–4159.CrossRefGoogle Scholar
Isganaitis, E, Woo, M, Ma, H, et al. Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice. Diabetes. 2014; 63(2), 688–700.10.2337/db13-0558CrossRefGoogle ScholarPubMed
Stefanidis, A, Spencer, SJ. Effects of neonatal overfeeding on juvenile and adult feeding and energy expenditure in the rat. PLoS One. 2012; 7(12), e51697.10.1371/journal.pone.0052130CrossRefGoogle ScholarPubMed
Cai, G, Dinan, T, Barwood, JM, et al. Neonatal overfeeding attenuates acute central pro-inflammatory effects of short-term high fat diet. Front Neurosci. 2015; 8, 446.10.3389/fnins.2014.00446CrossRefGoogle ScholarPubMed
de Queiroz, KB, Coimbra, RS, Ferreira, AR, et al. Molecular mechanism driving retroperitoneal adipocyte hypertrophy and hyperplasia in response to a high-sugar diet. Mol Nutr Food Res. 2014; 58(12), 2331–2341.10.1002/mnfr.201400241CrossRefGoogle ScholarPubMed
de Queiroz, KBarbosa, Evangelista, EA, Guerra-Sá, R. Metabolic imprinting induced by a high-sugar diet: effects on microRNA expression and insulin resistance in young rats. Mol Biol Rep. 2022; 49(8), 8173–8178.CrossRefGoogle Scholar
de Queiroz, KB, Rodovalho, GV, Guimarães, JB, et al. Endurance training blocks uncoupling protein 1 up-regulation in brown adipose tissue while increasing uncoupling protein 3 in the muscle tissue of rats fed with a high-sugar diet. Nutr Res. 2012; 32(9), 709–717.10.1016/j.nutres.2012.06.020CrossRefGoogle Scholar
Saltiel, AR. Insulin signaling in health and disease. J Clin Invest. 2021; 131(1), e142241.10.1172/JCI142241CrossRefGoogle ScholarPubMed
Ortega-Molina, A, Efeyan, A, Lopez-Guadamillas, E, et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab. 2012; 15(3), 382–394.10.1016/j.cmet.2012.02.001CrossRefGoogle ScholarPubMed
Corbi, G, Conti, V, Russomanno, G, et al. Adrenergic signaling and oxidative stress: a role for sirtuins? Front Physiol. 2013; 4, 324.10.3389/fphys.2013.00324CrossRefGoogle ScholarPubMed
Cannon, B, Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84(1), 277–359.CrossRefGoogle ScholarPubMed
Chouchani, ET, Kazak, L, Jedrychowski, MP, et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature. 2016; 532(7597), 112–116.10.1038/nature17399CrossRefGoogle ScholarPubMed
Lima-Leopoldo, AP, Leopoldo, AS, Silva, DC, et al. Dietary saturated fat and sugar reduce insulin signaling in cardiac muscle via oxidative stress. Can J Physiol Pharmacol. 2011; 89, 151–158.Google Scholar
de Queiroz, KB, Honorato-Sampaio, K, Rossoni Junior, JV, et al. Physical activity prevents alterations in mitochondrial ultrastructure and glucometabolic parameters in a high-sugar diet model. PLoS One. 2017; 12(2), e0172103.10.1371/journal.pone.0172103CrossRefGoogle Scholar
Rodrigues, B, Rosa, KT, Medeiros, A, et al. High-sucrose diet promotes insulin resistance and altered mitochondrial dynamics in skeletal muscle. J Nutr Biochem. 2020; 83, 108429.Google Scholar
Oliveira, DTD, Fernandes, IDC, Sousa, GGD, et al. High-sugar diet leads to obesity and metabolic diseases in ad libitum-fed rats irrespective of caloric intake. Arch Endocrinol Metab. 2020; 64(1), 71–81.10.20945/2359-3997000000199CrossRefGoogle ScholarPubMed
Spencer, SJ, Tilbrook, A. Neonatal overfeeding alters adult anxiety and stress responsiveness. Psychoneuroendocrino. 2009; 34(8), 1133–1143.10.1016/j.psyneuen.2009.02.013CrossRefGoogle ScholarPubMed
Miller, AL, Golledge, DR, Leach, MC. The influence of isoflurane anesthesia on the rat grimace scale. PLoS One. 2016; 11(11), e0166652.10.1371/journal.pone.0166652CrossRefGoogle ScholarPubMed
Maharani, NPR, Fadlyah, NA, Setyaningrum, DAW, et al. Effects of euthanasia on animal research. Vet Biomed Clin J. 2024; 6(1), 41–46.10.21776/ub.VetBioClinJ.2024.006.01.6CrossRefGoogle Scholar
Kersten, S. The impact of fasting on adipose tissue metabolism Biochim biophys acta mol cell biol lipids. 2023; 1868, 159262.10.1016/j.bbalip.2022.159262CrossRefGoogle ScholarPubMed
Nery, CDS, Pinheiro, IL, Muniz, GDS, et al. Murinometric measurements and feed efficiency in rats from litters reduced in lactation and whether or not subjected to swimming exercise. Braz J Sports Med. 2011; 17, 49–55.Google Scholar
Santos, SH, Fernandes, LR, Mario, EG, et al. Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes. 2008; 57(2), 340–347.10.2337/db07-0953CrossRefGoogle ScholarPubMed
Matthews, DR, Hosker, JP, Rudenski, AS, Naylor, BA, Treacher, DF, Turner, RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28(7), 412–417.CrossRefGoogle ScholarPubMed
Chen, H, Sullivan, G, Quon, MJ. Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model. Diabetes. 2005; 54(7), 1914–1925.10.2337/diabetes.54.7.1914CrossRefGoogle ScholarPubMed
Folch, J, Lees, M, Stanley, GS. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957; 226(1), 497–509.10.1016/S0021-9258(18)64849-5CrossRefGoogle ScholarPubMed
Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1), 265–275.CrossRefGoogle ScholarPubMed
Sander, H, Wallace, S, Plouse, R, Tiwari, S, Gomes, AV. Ponceau S waste: ponceau S staining for total protein normalization. Anal Biochem. 2019; 575, 44–53.10.1016/j.ab.2019.03.010CrossRefGoogle ScholarPubMed
Madesh, M, Balasubramanian, KA. Microtiter plate assay for superoxide dismutase using MTT reduction by superoxide. Indian J Biochem Biophys. 1998; 35(3), 184–188.Google ScholarPubMed
Aebi, H. Catalase in vitro. Methods Enzymol. 1984; 105, 121–126.10.1016/S0076-6879(84)05016-3CrossRefGoogle ScholarPubMed
Sedlak, J, Lindsay, RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968; 25, 192–205.10.1016/0003-2697(68)90092-4CrossRefGoogle ScholarPubMed
Levine, RL, Williams, JA, Stadtman, EP, Shacter, E. Carbonyl assay for determination of oxidatively modified proteins. Methods Enzymol. 1994; 233, 246–257.Google ScholarPubMed
Buege, JA, Aust, SD. Microsomal lipid peroxidation. Methods Enzymol. 1978; 52, 302–310.10.1016/S0076-6879(78)52032-6CrossRefGoogle ScholarPubMed
Conceição, EP, Franco, JG, Oliveira, E, et al. Oxidative stress programming in a rat model of postnatal early overnutrition—role of insulin resistance. J Nutr Biochem. 2013; 24(1), 704–712.10.1016/j.jnutbio.2012.02.010CrossRefGoogle Scholar
Rolnik, A, Olas, B, Szablińska-Piernik, J, et al. Antioxidant and anticoagulant properties of myo-inositol determined in ex vivo studies and gas chromatography analysis. Sci Rep. 2024; 14(1), 25633.10.1038/s41598-024-76527-2CrossRefGoogle ScholarPubMed
Dąbrowska, AM, Mirabegron, DJ. A selective β3-adrenergic receptor agonist, as a potential anti-obesity drug. J Clin Med. 2023; 12(21), 6897.10.3390/jcm12216897CrossRefGoogle ScholarPubMed
Conceição, EPS, Moura, EG, Trevenzoli, IH, et al. Neonatal overfeeding causes higher adrenal catecholamine content and basal secretion and liver dysfunction in adult rats. Eur J Nutr. 2013; 52(4), 1393–1404.10.1007/s00394-012-0448-8CrossRefGoogle ScholarPubMed
Margareto, J, Marti, A, Martínez, JA. Changes in UCP mRNA expression levels in brown adipose tissue and skeletal muscle after feeding a high-energy diet and relationships with leptin, glucose and PPARγ. J Nutr Biochem. 2001; 12(3), 130–137.10.1016/S0955-2863(00)00131-5CrossRefGoogle Scholar
Gjorgjieva, M, Mithieux, G, Rajas, F. Hepatic stress associated with pathologies characterized by disturbed glucose production. Cell Stress. 2019; 3(3), 86–99.CrossRefGoogle ScholarPubMed
Dornas, WC, Cardoso, LM, Silva, M, et al. Oxidative stress causes hypertension and activation of nuclear factor-κB after high-fructose and salt treatments. Sci Rep. 2017; 7(1), 46051.10.1038/srep46051CrossRefGoogle ScholarPubMed
Ziqubu, K, Dludla, PV, Mthembu, SX, et al. An insight into brown/beige adipose tissue whitening, a metabolic complication of obesity with the multifactorial origin. Front Endocrinol. 2023; 14, 1114767.10.3389/fendo.2023.1114767CrossRefGoogle ScholarPubMed
Pisoschi, AM, Pop, A. The role of antioxidants in the chemistry of oxidative stress: a review. Eur J Med Chem. 2015; 97, 55–74.10.1016/j.ejmech.2015.04.040CrossRefGoogle ScholarPubMed
Zhang, Z, Yang, D, Xiang, J, et al. Non-shivering thermogenesis signaling regulation and potential therapeutic applications of brown adipose tissue. Int J Biol Sci. 2021; 17(11), 2853–2870.10.7150/ijbs.60354CrossRefGoogle ScholarPubMed
Schreiber, R, Diwoky, C, Schoiswohl, G, et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab. 2017; 26(5), 753–763.10.1016/j.cmet.2017.09.004CrossRefGoogle Scholar
Li, Y, Fromme, T, Klingenspor, M. Meaningful respirometric measurements of UCP1-mediated thermogenesis. Biochimie. 2017; 134, 56–61.10.1016/j.biochi.2016.12.005CrossRefGoogle ScholarPubMed
Sanchez-Gurmaches, J, Tang, Y, Jespersen, NZ, et al. Brown fat AKT2 is a cold-induced kinase that stimulates chREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab. 2018; 27(1), 195–209.10.1016/j.cmet.2017.10.008CrossRefGoogle ScholarPubMed
Fischer, AW, Cannon, B, Nedergaard, J. Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study. Mol Metab. 2018; 7, 161–170.10.1016/j.molmet.2017.10.009CrossRefGoogle ScholarPubMed
Cao, W, Daniel, KW, Robidoux, J et al. P38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol. 2004; 24(7), 3057–3067.CrossRefGoogle Scholar
London, E, Stratakis, CA. The regulation of PKA signaling in obesity and in the maintenance of metabolic health. Pharmacol Ther. 2022; 237, 108113.10.1016/j.pharmthera.2022.108113CrossRefGoogle ScholarPubMed
Shabalina, IG, Vrbacký, M, Pecinová, A, et al. ROS production in brown adipose tissue mitochondria: the question of UCP1-dependence. Biochim Biophys Acta. 2014; 1837(12), 2017–2030.CrossRefGoogle Scholar
Sánchez-Garrido, MA, Castellano, JM, Ruiz-Pino, F, et al. Pubertal metabolic programming: sexually dimorphic responses to early nutritional challenges. Endocrinology. 2013; 154(9), 3387–3400.10.1210/en.2012-2157CrossRefGoogle ScholarPubMed
Palou, M, Priego, T, Sánchez, J, Palou, A, Picó, C. Sex and gender differences in developmental programming of metabolism. Mol Metab. 2018; 15, 8–19.Google Scholar
Costa, VMG, Andreazzi, AE, Bolotari, M, et al. Effect of postnatal overfeeding on reproductive parameters of male and female wistar rats. J Dev Orig Health Dis. 2019; 10(6), 667–675.10.1017/S2040174419000163CrossRefGoogle Scholar
Teicher, MH, Kenny, JT. Effect of reduced litter size on the suckling behaviour of developing rats. Nature. 1978; 275(5682), 644–646.10.1038/275644a0CrossRefGoogle ScholarPubMed
Enes-Marques, S, Giusti-Paiva, A. Litter size reduction accentuates maternal care and alters behavioral and physiological phenotypes in rat adult offspring. J Physiol Sci. 2018; 68(6), 789–798.CrossRefGoogle ScholarPubMed