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Cited by 57Birth, Development, and HealthAdipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and Metabolism

Developmental programming of offspring adipose tissue biology and obesity risk

Open access
Rodgers, Amanda, Sferruzzi-Perri, Amanda N.·2021·International Journal of Obesity
DOI 10.1038/s41366-021-00790-wPMC PMC8159749
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Abstract

Obesity is reaching epidemic proportions and imposes major negative health crises and an economic burden in both high and low income countries. The multifaceted nature of obesity represents a major health challenge, with obesity affecting a variety of different organs and increases the risk of many other noncommunicable diseases, such as type 2 diabetes, fatty liver disease, dementia, cardiovascular diseases, and even cancer. The defining organ of obesity is the adipose tissue, highlighting the need to more comprehensively understand the development and biology of this tissue to understand the pathogenesis of obesity. Adipose tissue is a miscellaneous and highly plastic endocrine organ. It comes in many different sizes and shades and is distributed throughout many different locations in the body. Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood. Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic. Recent studies show that environmental factors during prenatal and early stages of postnatal development have the capacity to programme the structure and function of adipose tissue, with implications for the development of obesity. This review summarizes the evidence for a role for early environmental factors, such as maternal malnutrition, hypoxia, and exposure to excess hormones and endocrine disruptors during gestation in the programming of adipose tissue and obesity in the offspring. We will also discuss the complexity of studying adipose tissue biology and the importance of appreciating nuances in adipose tissue, such as sexual dimorphism and divergent responses to metabolic and endocrine stimuli. Given the rising levels of obesity worldwide, understanding how environmental conditions in early life affects adipose tissue phenotype and the subsequent development of obesity is of absolute importance.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that suboptimal maternal environments—including malnutrition, low-protein diets, obesity/obesogenic diets, hypoxia, endocrine disruptors, glucocorticoids, and androgens—can program offspring adipose tissue structure, function, and obesity risk across mammalian species. It emphasizes that adipose tissue is a plastic, sexually dimorphic endocrine organ, while highlighting major gaps in BAT programming, sex-specific mechanisms, and transgenerational effects.

Key findings

  • Obesity is a global epidemic: 13% of adults were estimated to be obese in 2017, and in the UK the NHS cost of obesity was £6.1 billion in 2015, with a wider economic impact of £27 billion.
  • Adipose tissue is highly sexually dimorphic: the average human male body is 14% fat versus 27% in females; females typically show gynoid fat distribution and relatively benign obesity, whereas males show android distribution linked to higher risk of hypertension, insulin resistance, diabetes, dyslipidemia, and heart disease.
  • Maternal nutritional and caloric restriction, low-protein diets, and obesogenic/high-fat diets program offspring adiposity in divergent ways: low-protein diets tend to reduce birth weight and early adiposity but later increase fat accumulation and insulin resistance/hyperglycemia, while maternal obesity/high-fat diets consistently increase offspring adiposity, adipocyte hypertrophy, adipose inflammation, and decreased insulin signaling.
  • Non-nutritional exposures also program adipose biology: gestational hypoxia increases offspring adiposity and pro-inflammatory markers; BPA and phthalates increase adiposity and adipocyte size; excess glucocorticoids increase adiposity and reduce BAT UCP1; excess androgens alter female offspring WAT and BAT, including increased pro-inflammatory cytokines and dysfunctional BAT.
  • Proposed mechanisms include epigenetic changes (DNA methylation, histone modifications, noncoding RNAs) and altered mesenchymal stem cell fate toward adipogenesis; mesenchymal stem cells from infants of obese mothers show decreased β-catenin and greater in vitro adipocyte differentiation, with greater adiposity in 5-month-old infants.

Methods

  • Narrative review summarizing human epidemiological evidence and experimental animal studies on developmental programming of offspring adipose tissue and obesity risk.
  • Evidence covers maternal nutritional restriction, low-protein diets, maternal obesity/obesogenic diets, hypoxia, endocrine disruptors, glucocorticoids, and androgens, with findings organized in Tables 1–7 across species including mice, rats, guinea pigs, sheep, cows, pigs, baboons, rhesus monkeys, and humans.
  • Main analysis is qualitative synthesis of reported changes in adipose structure, molecular markers, whole-body metabolic outcomes, and proposed epigenetic/mesenchymal mechanisms; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated: most studies examined whole-body metabolism rather than adipose tissue directly; many analyzed only one fat depot; research focused on WAT, leaving BAT programming relatively unknown; sex effects are under-studied, with most studies using only male offspring and few comparing sexes; mechanisms remain largely unknown, with targeted molecular analyses rather than broad approaches such as RNA sequencing; transgenerational inheritance is largely unexplored.
  • Stated: the timing, duration, and severity of maternal manipulations are important but insufficiently studied; no studies were found exploring whether maternal obesity/obesogenic diets program offspring BAT; sex-specific effects of glucocorticoid over-exposure have not been explored.
  • Evident from the text: the review is not systematic and does not report formal quality assessment or meta-analytic synthesis; included studies vary widely by species, diet composition, exposure window, offspring age, and outcome measures, limiting direct comparability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41366-021-00790-w

Cites

162 of 162 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

71 of 146 cited sources checked · 22 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    In mice, the duration of maternal high-fat diet consumption has little effect on the magnitude of changes in offspring adiposity, as long as the diet was consumed within 9 weeks of mating.

    “Work in mice suggests that the duration of maternal high fat diet consumption has little effect on the magnitude of changes in offspring adiposity, as long as the diet was consumed within 9 weeks of mating [89].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Summerfield M, Zhou Y, Zhou T, Wu C, Alpini G, Zhang KK, et al. A long-term maternal diet transition from high-fat diet to normal fat diet during pre-pregnancy avoids adipose tissue inflammation in next generation. PLOS ONE. 2018;13:e0209053. source

      The Experimental design section says all high-fat groups received 12 weeks of maternal high-fat diet; what varied was the switch to normal-fat diet 1, 5, or 9 weeks before pregnancy. The Results report that the 1-week group had the highest relative visceral adipose mass, significantly above the 5- and 9-week groups. Thus the paper does not test differing durations of high-fat consumption, and its findings contradict the claim that timing within those nine weeks had little effect on offspring adiposity. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.
  • Premisecitation

    Like humans, female rodents harbor greater fat mass compared to males.

    “Like humans, female rodents harbor greater fat mass compared to males [52, 53].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [52] Grove KL, Fried SK, Greenberg AS, Xiao XQ, Clegg DJ. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. Int J Obes. 2010;34:989–1000. source
    • cites [53] Macotela Y, Boucher J, Tran TT, Kahn CR. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009;58:803–12. source

      The Discussion (page unavailable) says females have a higher percentage of body fat and refers to higher body fat in female humans and rodents. That does not establish greater absolute fat mass in female rodents; the Results section on adipose tissue weight reports that the measured fat pads were heavier in male mice. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    Ovariectomized female mice demonstrate a similar patterning of adipose tissue to males.

    “In addition, ovariectomized female mice demonstrate a similar patterning of adipose tissue to males [52].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Grove KL, Fried SK, Greenberg AS, Xiao XQ, Clegg DJ. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. Int J Obes. 2010;34:989–1000. source

      The Discussion (page not available) reports that, after a high-fat diet, ovariectomized females showed a trend toward more fat in intra-abdominal depots, resembling the trend in males. It does not establish broadly similar adipose-tissue patterning: inflammatory gene expression remained below male levels, and crown-like structures were intermediate. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Exposure to a diverse array of suboptimal maternal environments, including nutritionally unbalanced diets, low oxygen availability, and high body mass index (BMI) during gestation, modifies the risk of the offspring developing obesity.

    “Extensions of this work using human population and experimental animal data have shown that exposure to a diverse array of suboptimal maternal environments, including nutritionally unbalanced diets, low oxygen availability, and high body mass index (BMI) during gestation, modifies the risk of the offspring developing obesity [9, 10].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Sferruzzi-Perri AN, Camm EJ. The programming power of the placenta. Front Physiol. 2016;7:33. source

      The section on offspring metabolic systems reports increased adult-offspring adiposity after maternal calorie restriction, low-protein diets, and high-calorie diets; the section on cerebral structure and function also links calorie restriction to increased obesity risk. However, the passages on hypoxia describe birth weight, later growth, and cardiovascular effects—not offspring obesity—and the retrieved passages do not establish an effect of high maternal BMI or provide human population evidence for the stated obesity risk. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [10] Christoforou ER, Sferruzzi-Perri AN. Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress. Cell Mol Life Sci. 2020;77:4861–98. source

      The ‘Adipose lipid metabolism and morphology’ section links maternal undernutrition, protein restriction and high-fat diets to increased offspring body adiposity. The ‘Rodent models of developmental programming’ and ‘Alterations in DNA methylation in response to in utero stressors’ sections also discuss maternal obesity and gestational hypoxia, but link them to offspring metabolic disease or metabolic syndrome rather than specifically to obesity risk. The source therefore supports the broader metabolic-programming claim, but not the obesity-specific outcome for every exposure listed. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models of maternal diet manipulation are informative for human developmental programming of adipose tissue and obesity risk.
  • Premisecitation

    Larger species, like rabbits, sheep, cows, and humans are born with BAT stores, but most of these are gradually replaced by WAT after birth.

    “Contrastingly, larger species, like rabbits, sheep, cows, and humans are born with BAT stores, but most of these are gradually replaced by WAT after birth [13, 45, 46].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [13] Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17. source

      The Background says newborn humans have brown adipose tissue (BAT), and the Discussion reports less detectable BAT with increasing adult age. The paper does not address BAT at birth in rabbits, sheep, or cows, or say that BAT stores are gradually replaced by white adipose tissue after birth. The Discussion also reports that BAT remains present in many adults. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [45] Dawkins MJR, Hull D. Brown adipose tissue and the response of new-born rabbits to cold. J Physiol. 1964;172:216–38. source
    • cites [46] Hull D. The function of brown adipose tissue in the newborn. Biochem Soc Trans. 1976;4:226–8. source
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 8

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    Premisecitation

    In humans, maternal urinary BPA is associated with increased hip-to-waist ratios in the offspring, an effect that is more severe in females.

    “In humans, maternal urinary BPA has been associated with increased hip to waist ratios in the offspring, an affect that was more severe in females [109].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [109] Braun JM, Li N, Arbuckle TE, Dodds L, Massarelli I, Fraser WD, et al. Association between gestational urinary bisphenol a concentrations and adiposity in young children: The MIREC study. Environ Res. 2019;172:454–61. source

      The Results report an increase in waist-to-hip ratio, not hip-to-waist ratio; reversing the ratio reverses the direction of the association. The reported sex differences primarily concern waist circumference and skinfold thickness, rather than a demonstrated stronger ratio association in girls. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    The increase in adiposity from maternal nutrient restriction is related to an increase in brown and beige adipose tissue in guinea pigs, as well as adipocyte hypertrophy in cows and baboons.

    “Moreover, there is evidence that this increase in adiposity is related to an increase in brown and beige adipose tissue in particular species, namely guinea pigs [62], as well as adipocyte hypertrophy in other species, like cows and baboons [61, 63].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [62] Ashwell M, Purkins L, Cowen T, Day KC. Pre- and postnatal development of adipose tissue at four sites in the guinea pig: effect of maternal diet restriction during the second half of pregnancy. Ann Nutr Metab. 1987;31:197–210. source
    • cites [61] Long NM, Tousley CB, Underwood KR, Paisley SI, Means WJ, Hess BW, et al. Effects of early- to mid-gestational undernutrition with or without protein supplementation on offspring growth, carcass characteristics, and adipocyte size in beef cattle1. J Anim Sci. 2012;90:197–206. source
    • cites [63] Tchoukalova YD, Krishnapuram R, White UA, Burk D, Fang X, Nijland MJ, et al. Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction. Int J Obes. 2014;38:224–30. source

      The Results (Histology; page unavailable) report that maternal nutrient reduction promoted adipocyte hypertrophy in fetal baboons, primarily evident in males. But the Discussion suggests that nutrient-restricted male fetuses may have had less total adipose tissue, not increased adiposity; the paper therefore does not establish hypertrophy as an explanation for increased adiposity. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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    Premisecitation

    Enhanced adiposity is accompanied by changes in PPAR and UCP1/2 abundance in the adipose of offspring from undernourished mothers, and the timing of maternal nutrient restriction determines the nature of the molecular changes and level of adiposity.

    “Enhanced adiposity is also accompanied by changes in PPAR and UCP1/2 abundance in the adipose of offspring from undernourished mothers, however the timing of the maternal nutrient restriction seems to determine the nature of the molecular changes and level of adiposity [60, 63–65].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [60] Bispham J, Gardner DS, Gnanalingham MG, Stephenson T, Symonds ME, Budge H. Maternal nutritional programming of fetal adipose tissue development: differential effects on messenger ribonucleic acid abundance for uncoupling proteins and peroxisome proliferator-activated and prolactin receptors. Endocrinology. 2005;146:3943–9. source
    • cites [63] Tchoukalova YD, Krishnapuram R, White UA, Burk D, Fang X, Nijland MJ, et al. Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction. Int J Obes. 2014;38:224–30. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [64] Bispham Heasman, Clarke Ingleton. Stephenson, symonds. effect of maternal dexamethasone treatment and ambient temperature on prolactin receptor abundance in brown adipose and hepatic tissue in the foetus and new-born lamb. J Neuroendocrinol. 2001;11:849–56. source
    • cites [65] Budge H, Edwards LJ, McMillen IC, Bryce A, Warnes K, Pearce S, et al. Nutritional manipulation of fetal adipose tissue deposition and uncoupling protein 1 messenger RNA abundance in the sheep: differential effects of timing and duration. Biol Reprod. 2004;71:359–65. source

  • May combine two claims.

    Premisecitation

    Females typically have a gynoid fat distribution, where fat is stored around the hips and thighs, while males typically display an android form of fat distribution, where fat is stored around the waist.

    “Females typically have a gynoid fat distribution, where fat is stored around the hips and thighs, while males typically display an android form of fat distribution, where fat is stored around the waist [49, 50].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [49] Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differences in human adipose tissues—the biology of pear shape. Biol Sex Differ. 2012;3:13. source
    • cites [50] Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. Int J Obes. 2010;34:949–59. source

  • May combine two claims.

    Premisecitation

    Across the species surveyed, changes in offspring adiposity are accompanied by alterations in adipocyte size or number, insulin signaling and metabolic protein levels, including PPARγ, as well as inflammatory markers and leukocytes in the adipose tissue of the offspring born from low protein diet-fed mothers.

    “Across the species surveyed, changes in offspring adiposity are accompanied by alterations in adipocyte size or number, insulin signaling and metabolic protein levels, including PPARγ, as well as inflammatory markers and leukocytes in the adipose tissue of the offspring born from low protein diet-fed mothers [71, 72, 78, 82].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [71] Pan S, Jia Y, Yang X, Cai D, Liu Z, Song H, et al. Amino acid starvation-induced autophagy is involved in reduced subcutaneous fat deposition in weaning piglets derived from sows fed low-protein diet during gestation and lactation. Eur J Nutr. 2018;57:991–1001. source
    • cites [72] Tarry-Adkins JL, Aiken CE, Ashmore TJ, Ozanne SE. Insulin-signalling dysregulation and inflammation is programmed trans-generationally in a female rat model of poor maternal nutrition. Sci Rep. 2018;8:4014. source

      The Results (Anthropomorphic measurements; insulin-signalling and pro-inflammatory marker sections) report increased para-ovarian fat-pad weight, a shift in the proportion of small adipocytes, altered insulin-signalling proteins, and increased IL-1β in female F2 rats exposed to grand-maternal protein restriction. Mean adipocyte size did not change, and the paper does not establish the sentence’s claims about PPARγ, adipose-tissue leukocytes, or effects across species. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [78] Kim J, Choi A, Kwon YH. Maternal protein restriction altered insulin resistance and inflammation-associated gene expression in adipose tissue of young adult mouse offspring in response to a high-fat diet. Nutrients. 2020;12:1103. source

      The Results (§3.1; page unavailable) report increased relative adiposity and reduced adipose-tissue macrophage infiltration in offspring of low-protein-fed mice; the Discussion (§4; page unavailable) reports altered adipocyte size and lower inflammation and insulin resistance. This mouse study does not establish the claim across species, and the passages do not report altered PPARγ protein levels or directly measured insulin-signaling proteins. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [82] Xie L, Zhang K, Rasmussen D, Wang J, Wu D, Roemmich JN, et al. Effects of prenatal low protein and postnatal high fat diets on visceral adipose tissue macrophage phenotypes and IL-6 expression in Sprague Dawley rat offspring. PLOS ONE. 2017;12:e0169581. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Offspring from low protein fed mothers often display insulin resistance and hyperglycemia in adulthood.

    “However, offspring from low protein fed mothers accumulate greater amounts of fat as they mature [75, 76] and often display insulin resistance and hyperglycemia in adulthood [77, 78].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [77] Alessandra, Isadora, Marcia, Carlos. Protein restriction during gestation and/or lactation causes adverse transgenerational effects on biometry and glucose metabolism in F1 and F2 progenies of rats. Clin Sci. 2008;114:381–92. source
    • cites [78] Kim J, Choi A, Kwon YH. Maternal protein restriction altered insulin resistance and inflammation-associated gene expression in adipose tissue of young adult mouse offspring in response to a high-fat diet. Nutrients. 2020;12:1103. source

      The Discussion (page not provided) reports hyperglycemia in nine-month-old offspring of low-protein-fed mothers after long-term high-fat, high-sucrose feeding, supporting that part of the claim under a specific dietary condition. But Results §3.2 (page not provided) finds lower insulin-resistance markers in this study’s adult low-protein offspring than in controls fed a high-fat diet; the paper describes findings across studies as inconsistent, so it does not support the general claim that these offspring often display insulin resistance. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In humans, maternal obesity is associated with an increased risk of their child having increased adiposity during infancy and obesity in adulthood.

    “In humans, maternal obesity is associated with an increased risk of their child having increased adiposity during infancy and obesity in adulthood [85].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Kaar JL, Crume T, Brinton JT, Bischoff KJ, McDuffie R, Dabelea D. Maternal obesity, gestational weight gain, and offspring adiposity: the exploring perinatal outcomes among children study. J Pediatrics. 2014;165:509–15. source

      The Results report greater adiposity among offspring of overweight or obese mothers, but the children were studied at an average age of 10 years. The Discussion describes associations as early as ages 2–4, not infancy. The introductory passage says obese children tend to become obese adults, but does not establish an association between maternal obesity and offspring obesity in adulthood. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models of maternal diet manipulation are informative for human developmental programming of adipose tissue and obesity risk.

  • May combine two claims.

    Premisecitation

    Offspring from obese/high-fat diet-fed mothers show increased adiposity and adipocyte hypertrophy postnatally.

    “Offspring from obese/high-fat diet-fed mothers show increased adiposity [88–90] and adipocyte hypertrophy postnatally [89, 91].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [88] Boyle KE, Patinkin ZW, Shapiro ALB, Baker PR, Dabelea D, Friedman JE. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: The Healthy Start BabyBUMP Project. Diab. 2016;65:647–59. source

      The Results (Subject Characteristics; page unavailable) report higher percent fat mass at birth in infants of obese mothers than in infants of normal-weight mothers. The paper does not report maternal high-fat-diet exposure or postnatal adipocyte hypertrophy; its cell-culture findings concern adipogenic potential, not measured adipocyte size in offspring. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [89] Summerfield M, Zhou Y, Zhou T, Wu C, Alpini G, Zhang KK, et al. A long-term maternal diet transition from high-fat diet to normal fat diet during pre-pregnancy avoids adipose tissue inflammation in next generation. PLOS ONE. 2018;13:e0209053. source
    • cites [90] Lima MS, Perez GS, Morais GL, Santos LS, Cordeiro GS, Couto RD, et al. Effects of maternal high fat intake during pregnancy and lactation on total cholesterol and adipose tissue in neonatal rats. Braz J Biol. 2018;78:615–8. source
    • cites [91] Murabayashi N, Sugiyama T, Zhang L, Kamimoto Y, Umekawa T, Ma N, et al. Maternal high-fat diets cause insulin resistance through inflammatory changes in fetal adipose tissue. Eur J Obstet Gynaecol Reprod Biol. 2013;169:39–44. source
    • Rests on an assumption: Maternal obesity/obesogenic diets in animal models are relevant to human maternal obesity.

  • May combine two claims.

    Premisecitation

    Offspring from obese/high-fat diet-fed mothers often show increased inflammatory marker expression and a higher infiltration of macrophages and other immune cells in their adipose tissue, which may reflect lipotoxicity and likely contributed to the glucose intolerance seen in such offspring.

    “They also often show increased inflammatory marker expression and a higher infiltration of macrophages and other immune cells in their adipose tissue [89, 91, 92], which may reflect lipotoxicity and likely contributed to the glucose intolerance seen in such offspring.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [89] Summerfield M, Zhou Y, Zhou T, Wu C, Alpini G, Zhang KK, et al. A long-term maternal diet transition from high-fat diet to normal fat diet during pre-pregnancy avoids adipose tissue inflammation in next generation. PLOS ONE. 2018;13:e0209053. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [91] Murabayashi N, Sugiyama T, Zhang L, Kamimoto Y, Umekawa T, Ma N, et al. Maternal high-fat diets cause insulin resistance through inflammatory changes in fetal adipose tissue. Eur J Obstet Gynaecol Reprod Biol. 2013;169:39–44. source
    • cites [92] Chang E, Hafner H, Varghese M, Griffin C, Clemente J, Islam M, et al. Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation. Sci Rep. 2019;9:16027. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Maternal obesity/obesogenic diets in animal models are relevant to human maternal obesity.

  • May combine two claims.

    Premisecitation

    Overall, the available data suggest that maternal low protein diets have a complex effect on adipose tissue biology, with studies finding divergent molecular changes.

    “Overall, the available data suggest that maternal low protein diets have a complex effect on adipose tissue biology, with studies finding divergent molecular changes [71, 72].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [71] Pan S, Jia Y, Yang X, Cai D, Liu Z, Song H, et al. Amino acid starvation-induced autophagy is involved in reduced subcutaneous fat deposition in weaning piglets derived from sows fed low-protein diet during gestation and lactation. Eur J Nutr. 2018;57:991–1001. source
    • cites [72] Tarry-Adkins JL, Aiken CE, Ashmore TJ, Ozanne SE. Insulin-signalling dysregulation and inflammation is programmed trans-generationally in a female rat model of poor maternal nutrition. Sci Rep. 2018;8:4014. source
    • Rests on an assumption: Maternal low protein diet in animal models is a valid model for human low protein consumption during pregnancy.

  • May combine two claims.

    Premisecitation

    Studies of women who have undergone bariatric surgery show that siblings born of women post surgery displayed a reduced prevalence of obesity compared to those born before surgery, providing compelling evidence for a role for developmental programming rather than genetic factors in the maternal transmission of obesity.

    “Compelling evidence showing a role for developmental programming rather than genetic factors in the maternal transmission of obesity comes from studies of women who have undergone bariatric surgery to reduce weight; siblings born of women post surgery displayed a reduced prevalence of obesity compared to those born before surgery [86, 87].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [86] Smith J, Cianflone K, Biron S, Hould FS, Lebel S, Marceau S, et al. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metab. 2009;94:4275–83. source
    • cites [87] Guenard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, Vohl MC. Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proc Natl Acad Sci. 2013;110:11439–44. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the WAT of males from obese rats, there are alterations in DNA methylation of CpG sites proximal to C/EBP-β and Zfp423 genes, which is consistent with increased expression of key adipogenic regulators PPAR-γ, C/EBP-α, and C/EBP-β.

    “In the WAT of males from obese rats, there are alterations in DNA methylation of CpG sites proximal to C/EBP-β and Zfp423 genes, which encode key transcriptional factors initiating adipogenic commitment and is consistent with the increased expression of key adipogenic regulators, PPAR-γ, C/EBP-α, and C/EBP-β [139].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [139] Borengasser SJ, Zhong Y, Kang P, Lindsey F, Ronis MJJ, Badger TM, et al. Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. 2013;154:4113–25. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Neonatal exposure of female offspring to testosterone leads to increased BAT which is dysfunctional.

    “Exposure of female offspring to testosterone neonatally leads to increased BAT which is dysfunctional [136], although whether prenatal exposure also affects BAT phenotype postnatally has yet to be explored.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [136] Nohara K, Waraich RS, Liu S, Ferron M, Waget A, Meyers MS, et al. Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am J Physiol Endocrinol Metab. 2013;304:E1321–30. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Programmed changes in offspring adipose biology may be permanent, as an exercise intervention in mothers fed a high-fat diet did not prevent the increased adiposity or trigger beneficial changes in insulin signaling component expression in their fetuses.

    “some research suggests that programmed changes in offspring adipose biology may be permanent, as an exercise intervention in mothers fed a high-fat diet did not prevent the increased adiposity or trigger beneficial changes in insulin signaling component expression in their fetuses [95].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [95] Raipuria M, Bahari H, Morris MJ. Effects of maternal diet and exercise during pregnancy on glucose metabolism in skeletal muscle and fat of weanling rats. PLOS ONE. 2015;10:e0120980. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    PCOS increases the risk of type 2 diabetes and obesity in women, thus in utero androgen exposure may both directly and indirectly have an impact on adiposity in later life.

    “PCOS increases the risk of type 2 diabetes and obesity in women, thus in utero androgen exposure may both directly and indirectly have an impact on adiposity in later life [129, 130].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [129] Moran C, Arriaga M, Rodriguez G, Moran S. Obesity differentially affects phenotypes of polycystic ovary syndrome. Int J Endocrinol. 2012;2012:1–7. source

      Section 6.2 identifies PCOS as a risk factor for type 2 diabetes, and the Introduction and Section 4 associate PCOS with overweight or obesity. They do not establish that PCOS increases the risk of obesity. Section 12 says information about hormonal and metabolic factors during intrauterine life is scarce; it does not support the proposed direct or indirect effect of in utero androgen exposure on later-life adiposity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [130] Wang ET, Calderon-Margalit R, Cedars MI, Daviglus ML, Merkin SS, Schreiner PJ, et al. Polycystic ovary syndrome and risk for long-term diabetes and dyslipidemia. Obstet Gynecol. 2011;117:6–13. source

      The Results report higher odds of incident diabetes in women with PCOS, and the Introduction describes an association between PCOS and obesity. The paper does not establish that PCOS increases the risk of developing obesity; it also does not examine in utero androgen exposure or later-life adiposity, which the citing sentence presents as an inference. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Androgen exposure in utero is thought to be both a cause and a consequence of PCOS, impacting the transmission of the disease.

    “Therefore, androgen exposure in utero is thought to be both a cause and a consequence of PCOS, impacting the transmission of the disease [128].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [128] Abbott DH, Kraynak M, Dumesic DA, Levine JE. In utero androgen excess: a developmental commonality preceding polycystic ovary syndrome? Front Horm Res. 2019;53:1–17. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    In female offspring, excess androgen exposure changes the size of WAT adipocytes and increases chemokine and pro-inflammatory cytokine expression and dysregulated adiponectin expression, depending on the timing of exposure and WAT depot.

    “There is a change in the size of WAT adipocytes [132, 136] and an increase in chemokine and pro-inflammatory cytokine expression and dysregulated adiponectin expression, depending on the timing of the androgen exposure and WAT depot in female offspring [132, 137].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [132] Puttabyatappa M, Andriessen V, Mesquitta M, Zeng L, Pennathur S, Padmanabhan V. Developmental programming: impact of gestational steroid and metabolic milieus on mediators of insulin sensitivity in prenatal testosterone–treated female sheep. Endocrinology. 2017;158:2783–98. source
    • cites [136] Nohara K, Waraich RS, Liu S, Ferron M, Waget A, Meyers MS, et al. Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am J Physiol Endocrinol Metab. 2013;304:E1321–30. source

      The Results (page unavailable) report enlarged perigonadal adipocytes and lower serum adiponectin in neonatally androgenized female mice. The paper does not report increased chemokine or pro-inflammatory cytokine expression, adiponectin expression in WAT, or effects that vary by timing of androgen exposure and WAT depot. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [137] Gulan T, Yeernuer T, Sui S, Mayinuer N. A rat model of maternal polycystic ovary syndrome shows that exposure to androgens in utero results in dysbiosis of the intestinal microbiota and metabolic disorders of the newborn rat. Med Sci Monit. 2019;25:9377–91. source

      The Results section on adipose-tissue inflammation reports increased inflammatory cytokine expression in white adipose tissue of androgen-exposed female offspring. The Results section on serum hormones reports reduced circulating adiponectin and increased MCP-1, but not their expression in WAT. Our copy does not establish changes in adipocyte size or effects that depend on exposure timing or WAT depot. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    These changes in offspring adiposity following BPA/phthalate exposure are associated with enhanced adipocyte size, infiltration of inflammatory leukocytes, and elevated expression of lipogenic markers like PPAR-γ and SREBP.

    “In part, these changes are associated with enhanced adipocyte size, infiltration of inflammatory leukocytes, and elevated expression of lipogenic markers, like PPAR-γ and SREBP [113].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [113] Malaisé Y, Menard S, Cartier C, Gaultier E, Lasserre F, Lencina C, et al. Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to Bisphenol A precede obese phenotype development. Sci Rep. 2017;7:14472. source

      The Results section reports increased gonadal white-adipose-tissue weight and a higher percentage of inflammatory M1 macrophages in BPA-exposed offspring at PND170. It does not report increased adipocyte size or elevated PPAR-γ or SREBP expression, and the study concerns BPA rather than phthalate exposure. The same Results passage says only IL-17 expression increased among the adipose-tissue genes tested. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    There are differences in adipose tissue morphology and leukocyte influx, as well as metabolic phenotype, between exposed male and female offspring.

    “Of the studies that have, there are differences in adipose tissue morphology and leukocyte influx, as well as metabolic phenotype between exposed male and female offspring [92, 96].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [92] Chang E, Hafner H, Varghese M, Griffin C, Clemente J, Islam M, et al. Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation. Sci Rep. 2019;9:16027. source

      The Discussion (page not provided) says maternal obesity affected male offspring but not female offspring, supporting a sex difference in metabolic response. The Results on adipose morphology and macrophages (page not provided) examine male offspring only; they do not establish male–female differences in adipose morphology or leukocyte influx. The increased macrophages were predominantly resident CD11c− cells, rather than evidence of greater recruited-cell influx. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [96] Lemonnier D. Effect of age, sex, and site on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet. J Clin Investig. 1972;51:2907–15. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Developmental exposure to BPA is linked to enhanced levels of oxidative stress in the adipose of exposed offspring, and this effect was not prevented by a perinatal Mediterranean diet.

    “Developmental exposure to BPA has also been linked to enhanced levels of oxidative stress in the adipose of exposed offspring however, such an effect was not prevented by exposure to a perinatal Mediterranean diet that is known to offer protection against oxidative stress [114].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [114] Neier K, Marchlewicz EM, Bedrosian LD, Dolinoy DC, Harris C. Characterization of the mouse white adipose tissue redox environment and associations with perinatal environmental exposures to bisphenol A and high-fat diets. J Nutr Biochem. 2019;66:86–97. source

      The Results (page not provided) report a more oxidizing adipose redox measure in female offspring exposed to BPA, including those exposed to a perinatal Mediterranean high-fat diet. But the finding was sex-specific, and the Discussion notes that BPA’s effect was not statistically significant after adjustment. The claim overstates this measure as a general increase in adipose oxidative stress among exposed offspring. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    The differentiation of mesenchymal stem cells to adipocytes in vitro is increased and adiposity is greater in 5-month-old infants from obese mothers.

    “Consistent with this, the differentiation of mesenchymal stem cells to adipocytes in vitro was increased and adiposity greater in 5-month-old infants from obese mothers [88].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [88] Boyle KE, Patinkin ZW, Shapiro ALB, Baker PR, Dabelea D, Friedman JE. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: The Healthy Start BabyBUMP Project. Diab. 2016;65:647–59. source

      The Results report greater in-vitro adipogenesis in mesenchymal stem cells from infants of obese mothers and higher infant percent fat mass at birth. The Subjects methods specify that body composition was measured within 72 hours after birth, not at five months; the paper therefore does not support the claim's age qualifier. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    The placenta is the functional interface between mother and fetus and the main determinant of maternal nutrient, oxygen, and hormonal supply to the fetus during gestation.

    “The placenta is the functional interface between mother and fetus and the main determinant of maternal nutrient, oxygen, and hormonal supply to the fetus during gestation [9, 147].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Sferruzzi-Perri AN, Camm EJ. The programming power of the placenta. Front Physiol. 2016;7:33. source

      The sections on placental structure and transport describe the placenta as the materno-fetal interface through which oxygen and nutrients reach the fetus. The section on other essential placental functions says the placenta regulates exposure to circulating maternal hormones, but emphasizes its role as a barrier and its hormonal output into the mother. It does not establish that the placenta is the main determinant of maternal hormonal supply to the fetus. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [147] Sferruzzi-Perri AN, Lopez-Tello J, Napso T, Yong HEJ. Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models. Placenta. 2020;98:43–51. source

      The endocrine placenta and maternal metabolic alterations section (page unavailable) says placental hormones affect maternal metabolism and thereby the supply of nutrients for fetal growth. It does not establish that the placenta is the main determinant of fetal oxygen or hormonal supply; the hormones discussed are secreted into the mother. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mesenchymal stem cells from infants of obese mothers show a decrease in the abundance of β-catenin, which would favor adipocyte rather than myocyte differentiation.

    “In addition, mesenchymal stem cells from infants of obese mothers showed a decrease in the abundance of β-catenin, which would favor adipocyte rather than myocyte differentiation [88].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [88] Boyle KE, Patinkin ZW, Shapiro ALB, Baker PR, Dabelea D, Friedman JE. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: The Healthy Start BabyBUMP Project. Diab. 2016;65:647–59. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Methylation of multiple genes is aberrant in the visceral WAT of infant and adult offspring exposed to excess androgens, which likely contributed to the development of obesity and PCOS in the experimental model.

    “Finally, the methylation of multiple genes was aberrant in the visceral WAT of infant and adult offspring exposed to excess androgens, which likely contributed to the development of obesity and PCOS in the experimental model [133].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [133] Xu N, Kwon S, Abbott DH, Geller DH, Dumesic DA, Azziz R, et al. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-Like phenotypes in prenatally androgenized rhesus monkeys. PLoS ONE. 2011;6:e27286. source

      The Abstract reports differentially methylated loci in infant and adult visceral adipose tissue of prenatally androgenized rhesus monkeys, and the Discussion suggests epigenomic changes may contribute to PCOS-like traits. It does not establish that methylation contributed to obesity; the Discussion also says it cannot determine whether adult methylation changes are a cause or consequence of PCOS-like features. The indexed passages provide section labels but no page numbers. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Higher adiposity in infants of obese mothers is linked to increased lipid species content and lipid transport gene expression in differentiated adipocytes and elevated oxidative stress, lower amino acid concentrations, and expression of growth-promoting genes in their differentiated neonatal myocytes.

    “Higher adiposity in infants of obese mothers was also linked to increased lipid species content and lipid transport gene expression in differentiated adipocytes and elevated oxidative stress, lower amino acid concentrations and expression of growth-promoting genes in their differentiated neonatal myocytes [146].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [146] Baker PR 2nd, Patinkin ZW, Shapiro ALB, de la Houssaye BA, Janssen RC, Vanderlinden LA, et al. Altered gene expression and metabolism in fetal umbilical cord mesenchymal stem cells correspond with differences in 5-month-old infant adiposity gain. Sci Rep. 2017;7:18095. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Maternal obesity is associated with upregulated expression of miR-126, which negatively regulates insulin receptor substrate-1 (IRS1), and this is correlated with reduced IRS1 abundance and insulin sensitivity of the WAT in exposed offspring.

    “For example, maternal obesity was associated with upregulated expression of miR-126, which negatively regulates insulin receptor susbtrate-1 (IRS1) and this was correlated to reduced IRS1 abundance and insulin sensitivity of the WAT in exposed offspring [93].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [93] Fernandez-Twinn DS, Alfaradhi MZ, Martin-Gronert MS, Duque-Guimaraes DE, Piekarz A, Ferland-Mccollough D, et al. Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms. Mol Metab. 2014;3:325–33. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Premisecitation

    Adipose tissue is highly plastic and has the capacity for unlimited growth throughout adulthood.

    “Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood.”
    • Also stated in: § Adipose tissues · plain
      “The presence of preadipocytes in WAT allows it to be highly plastic and capable of producing more mature white adipocytes when necessary [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Prins JB, O’Rahilly S. Regulation of adipose cell number in man. Clin Sci. 1997;92:3–11. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adipose tissue is a dynamic endocrine organ vital to whole body homeostasis and metabolism.

    “Although initially thought of as inert storage sites for triacylglycerol, adipose tissue is now recognized as a dynamic endocrine organ vital to whole body homeostasis and metabolism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Fliers E, Kreier F, Voshol PJ, Havekes LM, Sauerwein HP, Kalsbeek A, et al. White adipose tissue: getting nervous. J Neuroendocrinol. 2003;15:1005–10. source

  • May combine two claims.

    Interpretationreasoning

    Adipose tissue is a sexually dimorphic tissue, which is influenced by sex hormones and modifies the risk of obesity.

    “Thus, adipose tissue is a sexually dimorphic tissue, which is influenced by sex hormones and modifies the risk of obesity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Human infants are born exceptionally fat, with fat making up ~15% of a neonate's body weight.

    “Human infants are born exceptionally fat [24], with fat making up ~15% of a neonate’s body weight.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Widdowson EM. Chemical composition of newly born mammals. Nat. 1950;166:626–8. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisereasoning

    The differences in adipose location between sexes are thought to be largely caused by estrogen, as postmenopausal women develop a more android distribution.

    “The differences in adipose location between sexes are thought to be largely caused by estrogen, as postmenopausal women develop a more android distribution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several strains of female mice are relatively resistant to obesity on a high-fat diet, but this protection can be removed by ovariectomy.

    “Furthermore, unlike their male counterparts, several strains of female mice are relatively resistant to obesity on a high-fat diet [54, 55], but this protection can be removed by ovariectomy [56, 57].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [54] Nishikawa S, Yasoshima A, Doi K, Nakayama H, Uetsuka K. Involvement of sex, strain and age factors in high fat diet-induced obesity in C57BL/6J and BALB/cA mice. Exp Anim. 2007;56:263–72. source
    • cites [55] Hwang L-L, Wang C-H, Li T-L, Chang S-D, Lin L-C, Chen C-P, et al. Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity. 2010;18:463–9. source
    • cites [56] Ludgero-Correia A, Aguila MB, Mandarim-De-Lacerda CA, Faria TS. Effects of high-fat diet on plasma lipids, adiposity, and inflammatory markers in ovariectomized C57BL/6 mice. Nutrition. 2012;28:316–23. source
    • cites [57] Blaustein JD, Gentry RT, Roy EJ, Wade GN. Effects of ovariectomy and estradiol on body weight and food intake in gold thioglucose-treated mice. Physiol Behav. 1976;17:1027–30. source

  • May combine two claims.

    Premisecitation

    Adipose tissue is a highly sexually dimorphic tissue, patterning men and women in different ways, and the risks associated with obesity are also sexually dimorphic.

    “Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Jackson A, Stanforth P, Gagnon J, Rankinen T, Leon A, Rao D, et al. The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study. Int J Obes. 2002;26:789–96. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The average human male body is comprised of 14% fat whereas the female body is comprised of 27% fat.

    “The average human male body is comprised of 14% fat whereas the female body is comprised of 27% fat [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Jackson A, Stanforth P, Gagnon J, Rankinen T, Leon A, Rao D, et al. The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study. Int J Obes. 2002;26:789–96. source

  • May combine two claims.

    Premisecitation

    Increased adiposity in women produces a relatively benign form of obesity, whereas in males it is associated with higher risk for hypertension, insulin resistance, diabetes, dyslipidemia, and heart disease.

    “Increased adiposity in women produces a relatively benign form of obesity, whereas in males it is associated with higher risk for hypertension, insulin resistance, diabetes, dyslipidemia, and heart disease [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Pi-Sunyer FX. The epidemiology of central fat distribution in relation to disease. Nutr Rev. 2004;62:S120–S6. source

  • May combine two claims.

    Interpretationreasoning

    The greater propensity to become obese after maternal nutrient restriction may reflect metabolic adaptations to optimize growth when nutrient supply is limited in utero, but may be mal-adaptive and lead to excess storage of nutrients when nutrient supply is not limited postnatally.

    “Thus, the greater propensity to become obese may reflect metabolic adaptations to optimize growth when nutrient supply is limited in utero, but may be mal-adaptive and lead to excess storage of nutrients when nutrient supply is not limited postnatally.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Animal studies assessing the effect of maternal obesity/obesogenic diets on offspring adiposity broadly support human association data and show consistent outcomes across species.

    “Animal studies assessing the effect of maternal obesity/obesogenic diets on offspring adiposity broadly seem to support human association data and show consistent outcomes across species (Table 3).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Maternal obesity/obesogenic diets in animal models are relevant to human maternal obesity.

  • May combine two claims.

    Premisecitation

    Calorically restricting offspring exposed to a maternal low protein diet during gestation prevents the programming of increased adiposity postnatally, although molecular changes are still evident in the adipose tissue.

    “However, data from pigs has shown that calorically restricting offspring exposed to a maternal low protein diet during gestation prevents the programming of increased adiposity postnatally, although molecular changes are still evident in the adipose tissue [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] DuPriest EA, Lin B, Kupfer P, Sekiguchi K, Bhusari A, Quackenbush A, et al. Effects of postweaning calorie restriction on accelerated growth and adiponectin in nutritionally programmed microswine offspring. Am J Physiol Regul Integr Comp Physiol. 2018;315:R354–r68. source

  • May combine two claims.

    Premisecitation

    Offspring of low protein diet-fed mothers show increased BAT thermogenic activity and UCP1 expression, which may provide some explanation for their initial protection against high-fat-diet-induced obesity as young adults.

    “Finally, although less explored, offspring of low protein diet-fed mothers show increased BAT thermogenic activity and UCP1 expression [79], which may provide some explanation for their initial protection against high-fat-diet-induced obesity as young adults.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Dumortier O, Roger E, Pisani DF, Casamento V, Gautier N, Lebrun P, et al. Age-dependent control of energy homeostasis by brown adipose tissue in progeny subjected to maternal diet–induced fetal programming. Diabetes. 2017;66:627–39. source

  • May combine two claims.

    Premisecitation

    The timing of a nutrient restriction in sheep plays a role in determining the offspring outcome: exposure up to day 110 of sheep gestation promotes adipose tissue deposition in the fetal lamb at term, whereas continuing the nutrient restriction after this time decreases adipose tissue mass.

    “Symonds et al. found the timing of a nutrient restriction in sheep plays a role in determining the offspring outcome [26]. They found that exposure to maternal nutrient restriction up to day 110 of sheep gestation (term = 145 days) promoted adipose tissue deposition in the fetal lamb at term, whereas continuing the nutrient restriction after this time decreased adipose tissue mass.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Symonds ME, Pearce S, Bispham J, Gardner DS, Stephenson T. Timing of nutrient restriction and programming of fetal adipose tissue development. Proc Nutr Soc. 2004;63:397–403. source

  • May combine two claims.

    Premisecitation

    Increased adiposity despite exposure to maternal nutrient restriction is accompanied by an increased abundance of IGF receptors, suggesting enhanced adipose tissue sensitivity to the anabolic effects of IGFs.

    “Increased adiposity despite exposure to maternal nutrient restriction was accompanied by an increased abundance of IGF receptors, suggesting enhanced adipose tissue sensitivity to the anabolic effects of IGFs [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Teruel T, Valverde AM, Benito M, Lorenzo M. Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyteprimary cultures. Biochem J. 1996;319:627–32. source

  • May combine two claims.

    Interpretationcitation

    Nutrient supply in utero is important in determining offspring adiposity, with possible consequences for the offspring in subsequent generations.

    “These data highlight the importance of nutrient supply in utero in determining offspring adiposity, with possible consequences for the offspring in subsequent generations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exposure to hypoxia during intrauterine development is associated with molecular changes, including enhanced UCP1, DIO, and PPARγ expression in the adipose of sheep fetuses, suggesting the adipose may be programmed towards the beige phenotype.

    “Exposure to hypoxia during intrauterine development was also associated with molecular changes, including enhanced UCP1, DIO, and PPARγ expression in the adipose of sheep fetuses, suggesting the adipose may be programmed towards the beige phenotype [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Myers DA, Hanson K, Mlynarczyk M, Kaushal KM, Ducsay CA. Long-term hypoxia modulates expression of key genes regulating adipose function in the late-gestation ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1312–R8. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Across a variety of mammalian species, the impacts of certain manipulations, such as low protein diet, remain relatively consistent, increasing the reliability of this data.

    “Across a variety of mammalian species, the impacts of certain manipulations, such as low protein diet remains relatively consistent increasing the reliability of this data.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.
    • Rests on an assumption: The associations between maternal exposures and offspring adipose changes observed in the reviewed studies reflect causal programming rather than confounding or reverse causation.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Certain adipose pads, particularly the subcutaneous adipose, vary with offspring sex.

    “In addition, certain adipose pads, particularly the subcutaneous adipose vary with offspring sex.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Interpretationnone given

    The majority of studies analyse only one fat depot, and these depots can vary greatly and are reflective of the organ they are associated with.

    “The majority of studies also analyse only one fat depot and as discussed, these can vary greatly and are reflective of the organ they are associated with.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The impact of sex on the fetal programming of adipose tissue has been relatively under-studied.

    “The impact of sex on the fetal programming of adipose tissue has been relatively under-studied.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mice, female progeny of obese dams exposed to high-fat diet displayed obesity and high levels of WAT inflammation in association with hypomethylation at certain inflammatory genes for three generations.

    “For example, in mice, female progeny of obese dams exposed to high-fat diet displayed obesity and high levels of WAT inflammation in association with hypomethylation at certain inflammatory genes for three generations [153].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Ding Y, Li J, Liu S, Zhang L, Xiao H, LI J, et al. DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding. Int J Obes. 2014;38:198–204. source
    • Rests on an assumption: Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

  • May combine two claims.

    Interpretationnone given

    The majority of studies only investigated male offspring, and of the studies that do include female offspring, very few compare sexes.

    “The majority of the studies only investigated male offspring and of the studies that do include female offspring, very few compare sexes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    This 'deprogramming' of offspring phenotype via such an approach may prove to be a promising strategy to overcome the transgenerational transmission of obesity and help curb the current obesity epidemic and the high costs to health services worldwide.

    “This “deprogramming” of offspring phenotype via such an approach may prove to be a promising strategy to overcome the transgenerational transmission of obesity and help curb the current obesity epidemic and the high costs to health services worldwide.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The associations between maternal exposures and offspring adipose changes observed in the reviewed studies reflect causal programming rather than confounding or reverse causation.
    • Rests on an assumption: Adipose tissue changes such as adipocyte size, inflammation, and gene expression are valid indicators of obesity risk and metabolic dysfunction in humans.

  • May combine two claims.

    Interpretationnone given

    The majority of investigations available studied programmed changes in whole body metabolism, while the adipose tissue was examined in a very limited capacity.

    “However, broadly speaking, while the majority of investigations available studied programmed changes in whole body metabolism, the adipose tissue was examined in a very limited capacity.”
    Quote in the paperSubstantial claim
51 of 51

  • The paper relies on this without support.

    Findings from animal models of maternal diet manipulation are informative for human developmental programming of adipose tissue and obesity risk.

    “Extensions of this work using human population and experimental animal data have shown that exposure to a diverse array of suboptimal maternal environments, including nutritionally unbalanced diets, low oxygen availability, and high body mass index (BMI) during gestation, modifies the risk of the offspring developing obesity [9, 10].”

  • The paper relies on this without support.

    Maternal low protein diet in animal models is a valid model for human low protein consumption during pregnancy.

    “Studying the impact of gestational exposure to maternal low protein foods, may help to understand the recent rise in the rates of obesity and other metabolic diseases in many countries [68].”

  • The paper relies on this without support.

    Maternal obesity/obesogenic diets in animal models are relevant to human maternal obesity.

    “Animal studies assessing the effect of maternal obesity/obesogenic diets on offspring adiposity broadly seem to support human association data and show consistent outcomes across species (Table 3).”

  • The paper relies on this without support.

    Findings from animal models about maternal manipulations and offspring adipose biology are relevant to human developmental programming of obesity risk.

    “Across a variety of mammalian species, the impacts of certain manipulations, such as low protein diet remains relatively consistent increasing the reliability of this data.”

  • The paper relies on this without support.

    The associations between maternal exposures and offspring adipose changes observed in the reviewed studies reflect causal programming rather than confounding or reverse causation.

    “Alterations to the in utero environment as a result of suboptimal maternal conditions are related to programmed changes in the development, structure, and function of adipose tissue in the offspring.”

  • The paper relies on this without support.

    Adipose tissue changes such as adipocyte size, inflammation, and gene expression are valid indicators of obesity risk and metabolic dysfunction in humans.

    “The placenta likely plays a major role in mediating the programmed alterations in offspring adipose development and function, and hence, susceptibility to develop obesity.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Gestational-glucocorticoid table includes exposure during suckling

    Minor

    Table 6 is labeled as covering excess glucocorticoids during gestation, but its Weiler et al. row describes dexamethasone given in milk on postnatal days 5-20.

  • Gestational-androgen table includes postnatal exposure

    Minor

    Table 7 is labeled as covering androgen exposure during gestation, but it includes an intervention given after birth.

  • Sequential protein diets have overlapping date ranges

    Minor

    The row describes a low-protein diet followed by a high-protein diet, but the stated high-protein period begins on GD 94 while the first period continues through GD 180. The periods overlap rather than occurring sequentially.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Vernon RG, Flint DJ, Stock MJ, Cinti, S. Encyclopedia of Food Science and Nutrition. 2nd Edition. Caballero B, Finglas P, Toldra F, editors. Massachusetts: Academic Press; 2003.

Cited by

Sorted by citations

Related

Authors
Rodgers, A., & Sferruzzi-Perri, A. N.
Affiliations
University of Cambridge (GB)
Corresponding author
Sferruzzi-Perri, Amanda N.
ORCID
Sferruzzi-Perri, Amanda N.
Venue
International Journal of Obesity
Publisher
Springer Science and Business Media LLC
Published
2021-03-23
Volume
45
Issue
6
Pages
1170-1192
ISSN
  • 0307-0565 (ISSN-L)
  • 1476-5497
DOI
10.1038/s41366-021-00790-w
PMC
PMC8159749
OpenAlex
W3139037035
Semantic Scholar
2687179b73c46ed7199a5b3188780adacbb673f0
Cited by
57
References
162
Citations by year
2026: 7 · 2025: 10 · 2024: 10 · 2023: 10 · 2022: 16 · 2021: 4
FWCI
9.08
Type
journal article
Language
en
Update notices
correction (2021-05-10)
Open access
Licence
Locations
  • International Journal of Obesity (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
Funders
  • Academy of Medical Sciences (SBF002\1028)
  • Lister Institute of Preventive Medicine
  • Academy of Natural Sciences of Drexel University
  • Medical Research Council (MR/R022690/1)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
developmental programming, adipose tissue, obesity risk, maternal malnutrition, hypoxia, endocrine disruptors, sexual dimorphism, adipose tissue endocrine function, adipose tissue plasticity
MeSH terms
Adipose Tissue, Animals, Female, Humans, Obesity, Pregnancy, Risk Factors, Maternal Nutritional Physiological Phenomena, Mice, Rats, Pediatric Obesity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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