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Perinatal overnutrition exacerbates adipose tissue inflammation caused by high-fat feeding in C57BL/6J mice.

Kayser BD, Goran MI, Bouret SG - PLoS ONE (2015)

Bottom Line: Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals.Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice.Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Human and Evolutionary Biology Program, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, United States of America; Department of Preventive Medicine, Keck School of Medicine, Childhood Obesity Research Center, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT Arg1 and Tlr4 expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.

No MeSH data available.


Related in: MedlinePlus

Neonatal overfeeding promotes rapid weight gain and increases adiposity without causing WAT inflammation at weaning.A: Pre-weaning growth curves (body weights) of mice raised in normal litters (NL) or small litters (SL) (n = 19–25 per group from ≥ 9 litters). B-C: Mass (B) and mean adipocyte areas (C) of epididymal (eWAT) and subcutaneous (sWAT) adipose tissue of P21 SL and NL mice (n = 4–5 per group from ≥ 5 litters). D-E: Representative images showing adipocyte morphology (immunostained for perilipin, green fluorescence) and F4/80-immunoreactive cells (red fluorescence) in eWAT (D) and sWAT (E) of NL and SL mice at P21. F: Quantification of F4/80-immunoreactive cells in eWAT (D) and sWAT (E) of NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). G-H: Relative gene expression of macrophage markers (G) and cytokines (H) in sWAT at P21. I-K: Plasma levels of TNF-α (I), glucose (J), and insulin (K) in NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL. Scale bar, 100 μm.
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pone.0121954.g001: Neonatal overfeeding promotes rapid weight gain and increases adiposity without causing WAT inflammation at weaning.A: Pre-weaning growth curves (body weights) of mice raised in normal litters (NL) or small litters (SL) (n = 19–25 per group from ≥ 9 litters). B-C: Mass (B) and mean adipocyte areas (C) of epididymal (eWAT) and subcutaneous (sWAT) adipose tissue of P21 SL and NL mice (n = 4–5 per group from ≥ 5 litters). D-E: Representative images showing adipocyte morphology (immunostained for perilipin, green fluorescence) and F4/80-immunoreactive cells (red fluorescence) in eWAT (D) and sWAT (E) of NL and SL mice at P21. F: Quantification of F4/80-immunoreactive cells in eWAT (D) and sWAT (E) of NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). G-H: Relative gene expression of macrophage markers (G) and cytokines (H) in sWAT at P21. I-K: Plasma levels of TNF-α (I), glucose (J), and insulin (K) in NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL. Scale bar, 100 μm.

Mentions: To study the consequences of early postnatal overnutrition, we used a mouse model of divergent litter size. As expected, SL rearing was associated with changes in pre-weaning growth, as revealed by a significantly higher body weight in SL compared to NL mice starting at P4 (Fig 1A). At weaning, SL pups remained 20% heavier compared to NL pups (P<0.001 at P20; Fig 1A). In addition, epididymal (eWAT) and subcutaneous fat (sWat; i.e., inguinal + paracostal) masses were 4.5-fold and 3.6-fold increased, respectively, in P21 mice compared to control NL animals (Fig 1B). This increase in fat mass in weanling SL mice was accompanied by a 3-fold increase in adipocyte area (P<0.01; Fig 1C–1E). No differences in adipocyte number were detected between NL and SL mice in either eWAT or sWAT (S1 Fig). We next investigated adipose tissue macrophage infiltration using immunostaining for the macrophage marker F4/80. A 2.3-fold increase in the number of F4/80-positive cells was found in eWAT (P<0.05) and sWAT (P<0.01) of P21 SL mice as compared to control NL mice (Fig 1D–1F). However, CLS were undetected in both groups. Because obesity induces a phenotypic switch in adipose tissue macrophage polarization from an M2-polarized state to an M1 pro-inflammatory state [23], we also assessed M1- and M2-related gene expression in sWAT of SL and NL at P21. mRNA expression of the anti-inflammatory gene Arg1 was 5.4-fold increased (Fig 1G; P<0.05) in SL animals whereas Il10 gene expression was undetectable (Fig 1H). There were no differences in the expression of the proinflammatory genes Itgax or Tnfa, whereas TLR4 (P<0.05) was expressed 2-fold higher in SL mice (Fig 1G–1H). Consistent with the idea that neonatal overnutrition does not cause marked WAT inflammation at weaning, SL rearing had no effect on random-fed circulating levels of TNF-α, glucose, or insulin (Fig 1I–1K).


Perinatal overnutrition exacerbates adipose tissue inflammation caused by high-fat feeding in C57BL/6J mice.

Kayser BD, Goran MI, Bouret SG - PLoS ONE (2015)

Neonatal overfeeding promotes rapid weight gain and increases adiposity without causing WAT inflammation at weaning.A: Pre-weaning growth curves (body weights) of mice raised in normal litters (NL) or small litters (SL) (n = 19–25 per group from ≥ 9 litters). B-C: Mass (B) and mean adipocyte areas (C) of epididymal (eWAT) and subcutaneous (sWAT) adipose tissue of P21 SL and NL mice (n = 4–5 per group from ≥ 5 litters). D-E: Representative images showing adipocyte morphology (immunostained for perilipin, green fluorescence) and F4/80-immunoreactive cells (red fluorescence) in eWAT (D) and sWAT (E) of NL and SL mice at P21. F: Quantification of F4/80-immunoreactive cells in eWAT (D) and sWAT (E) of NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). G-H: Relative gene expression of macrophage markers (G) and cytokines (H) in sWAT at P21. I-K: Plasma levels of TNF-α (I), glucose (J), and insulin (K) in NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL. Scale bar, 100 μm.
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pone.0121954.g001: Neonatal overfeeding promotes rapid weight gain and increases adiposity without causing WAT inflammation at weaning.A: Pre-weaning growth curves (body weights) of mice raised in normal litters (NL) or small litters (SL) (n = 19–25 per group from ≥ 9 litters). B-C: Mass (B) and mean adipocyte areas (C) of epididymal (eWAT) and subcutaneous (sWAT) adipose tissue of P21 SL and NL mice (n = 4–5 per group from ≥ 5 litters). D-E: Representative images showing adipocyte morphology (immunostained for perilipin, green fluorescence) and F4/80-immunoreactive cells (red fluorescence) in eWAT (D) and sWAT (E) of NL and SL mice at P21. F: Quantification of F4/80-immunoreactive cells in eWAT (D) and sWAT (E) of NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). G-H: Relative gene expression of macrophage markers (G) and cytokines (H) in sWAT at P21. I-K: Plasma levels of TNF-α (I), glucose (J), and insulin (K) in NL and SL mice at P21 (n = 4–5 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL. Scale bar, 100 μm.
Mentions: To study the consequences of early postnatal overnutrition, we used a mouse model of divergent litter size. As expected, SL rearing was associated with changes in pre-weaning growth, as revealed by a significantly higher body weight in SL compared to NL mice starting at P4 (Fig 1A). At weaning, SL pups remained 20% heavier compared to NL pups (P<0.001 at P20; Fig 1A). In addition, epididymal (eWAT) and subcutaneous fat (sWat; i.e., inguinal + paracostal) masses were 4.5-fold and 3.6-fold increased, respectively, in P21 mice compared to control NL animals (Fig 1B). This increase in fat mass in weanling SL mice was accompanied by a 3-fold increase in adipocyte area (P<0.01; Fig 1C–1E). No differences in adipocyte number were detected between NL and SL mice in either eWAT or sWAT (S1 Fig). We next investigated adipose tissue macrophage infiltration using immunostaining for the macrophage marker F4/80. A 2.3-fold increase in the number of F4/80-positive cells was found in eWAT (P<0.05) and sWAT (P<0.01) of P21 SL mice as compared to control NL mice (Fig 1D–1F). However, CLS were undetected in both groups. Because obesity induces a phenotypic switch in adipose tissue macrophage polarization from an M2-polarized state to an M1 pro-inflammatory state [23], we also assessed M1- and M2-related gene expression in sWAT of SL and NL at P21. mRNA expression of the anti-inflammatory gene Arg1 was 5.4-fold increased (Fig 1G; P<0.05) in SL animals whereas Il10 gene expression was undetectable (Fig 1H). There were no differences in the expression of the proinflammatory genes Itgax or Tnfa, whereas TLR4 (P<0.05) was expressed 2-fold higher in SL mice (Fig 1G–1H). Consistent with the idea that neonatal overnutrition does not cause marked WAT inflammation at weaning, SL rearing had no effect on random-fed circulating levels of TNF-α, glucose, or insulin (Fig 1I–1K).

Bottom Line: Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals.Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice.Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Human and Evolutionary Biology Program, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, United States of America; Department of Preventive Medicine, Keck School of Medicine, Childhood Obesity Research Center, University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT Arg1 and Tlr4 expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.

No MeSH data available.


Related in: MedlinePlus