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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 overnutrition exacerbates HFD-induced expression of pro-inflammatory genes.A-B: Relative gene expression pro-inflammatory (A) and anti-inflammatory (B) markers in eWAT of NL and SL fed a high-fat diet (HFD) (n = 5–8 per group from 5–8 litters). C: Serum concentrations of adipokines/cytokines (n = 4–8 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL-HFD; ΔΔ P<0.01, ΔΔΔ P<0.001 for Diet main-effect.
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pone.0121954.g005: Neonatal overnutrition exacerbates HFD-induced expression of pro-inflammatory genes.A-B: Relative gene expression pro-inflammatory (A) and anti-inflammatory (B) markers in eWAT of NL and SL fed a high-fat diet (HFD) (n = 5–8 per group from 5–8 litters). C: Serum concentrations of adipokines/cytokines (n = 4–8 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL-HFD; ΔΔ P<0.01, ΔΔΔ P<0.001 for Diet main-effect.

Mentions: We next evaluated WAT inflammation in various fat pads of adult SL and NL mice fed a chow or a HFD. We first performed F4/80 staining to detect macrophage infiltration and the presence of CLS (Fig 4A–4B). Consistent with the low-inflammatory potential of low-fat feeding, CLS were rare in the eWAT, rWAT, and iWAT of chow fed NL and SL (Fig 4A). Moreover, there was no marked difference in the number of CLS between NL-Chow and SL-Chow (Fig 4A). However, when fed a HFD, SL mice displayed 3–8 times greater CLS counts in eWAT (P<0.001), rWAT (P<0.001), and iWAT (P<0.05) compared to NL-HFD mice (Fig 4B–4C). To further confirm macrophage infiltration in SL-HFD mice, we quantified total CD45+CD64+ macrophages in eWAT using flow cytometry. As expected, the total number of macrophages was not different between SL-chow and NL-chow mice (Fig 4F). However, on HFD, SL mice displayed twice as many CD45+CD64+ cells compared to NL-HFD mice (PSize X Diet<0.01; pairwise P<0.05; Fig 4F). Histological examination confirms that CLS predominately contain CD11c+ M1 macrophages, while CD301+ macrophages are identified as more diffuse isolated cells (Fig 4E). To better characterize the phenotype of adipose tissue macrophages, we next sorted CD45+CD64+ macrophages based on heterogeneous expression of CD11c and CD301. The number of CD11c+ macrophages was 3.8-fold higher in SL-HFD mice compared to NL-HFD (P<0.01; Fig 4F). In contrast, the number of CD301+ macrophages was reduced by 40% in the HFD groups (PDiet<0.01), with no additional effect of litter size (Fig 4F). These findings confirmed that the increased number of macrophages observed in the eWAT of SL-HFD mice is attributed to an increased number of M1 macrophages. Consistent with these findings, mRNA expression of pro-inflammatory genes, such as Il6, Tnfa, and Ccl2 (MCP-1) were up-regulated by 4.5 (P<0.05), 3.6 (P<0.05), and 5.1 (P<0.01) times, respectively, in eWAT of SL-HFD compared to NL-HFD mice (Fig 5A). Similar to the P22 animals, Tlr4 expression in SL-HFD was 1.7 times that of NL-HFD (P<0.05; Fig 5A). In addition, Arg1 mRNA expression was 6-fold increased in SL-HFD animals (P<0.01), but surprisingly, Il10 mRNA expression was not different between SL-HFD and NL-HFD mice (Fig 5B). Similarly, circulating concentrations of IL-6, TNF-α, MCP-1, and resistin were 2-, 1.1-, 1.7-, and 3.3-fold increased in HFD animals compared to chow fed mice (PDiet<0.001; Fig 5C). However, there were no additional effects of litter size on these circulating cytokines or resistin (Fig 5C).


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 overnutrition exacerbates HFD-induced expression of pro-inflammatory genes.A-B: Relative gene expression pro-inflammatory (A) and anti-inflammatory (B) markers in eWAT of NL and SL fed a high-fat diet (HFD) (n = 5–8 per group from 5–8 litters). C: Serum concentrations of adipokines/cytokines (n = 4–8 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL-HFD; ΔΔ P<0.01, ΔΔΔ P<0.001 for Diet main-effect.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383546&req=5

pone.0121954.g005: Neonatal overnutrition exacerbates HFD-induced expression of pro-inflammatory genes.A-B: Relative gene expression pro-inflammatory (A) and anti-inflammatory (B) markers in eWAT of NL and SL fed a high-fat diet (HFD) (n = 5–8 per group from 5–8 litters). C: Serum concentrations of adipokines/cytokines (n = 4–8 per group from ≥ 4 litters). *P<0.05 and **P<0.01 versus NL-HFD; ΔΔ P<0.01, ΔΔΔ P<0.001 for Diet main-effect.
Mentions: We next evaluated WAT inflammation in various fat pads of adult SL and NL mice fed a chow or a HFD. We first performed F4/80 staining to detect macrophage infiltration and the presence of CLS (Fig 4A–4B). Consistent with the low-inflammatory potential of low-fat feeding, CLS were rare in the eWAT, rWAT, and iWAT of chow fed NL and SL (Fig 4A). Moreover, there was no marked difference in the number of CLS between NL-Chow and SL-Chow (Fig 4A). However, when fed a HFD, SL mice displayed 3–8 times greater CLS counts in eWAT (P<0.001), rWAT (P<0.001), and iWAT (P<0.05) compared to NL-HFD mice (Fig 4B–4C). To further confirm macrophage infiltration in SL-HFD mice, we quantified total CD45+CD64+ macrophages in eWAT using flow cytometry. As expected, the total number of macrophages was not different between SL-chow and NL-chow mice (Fig 4F). However, on HFD, SL mice displayed twice as many CD45+CD64+ cells compared to NL-HFD mice (PSize X Diet<0.01; pairwise P<0.05; Fig 4F). Histological examination confirms that CLS predominately contain CD11c+ M1 macrophages, while CD301+ macrophages are identified as more diffuse isolated cells (Fig 4E). To better characterize the phenotype of adipose tissue macrophages, we next sorted CD45+CD64+ macrophages based on heterogeneous expression of CD11c and CD301. The number of CD11c+ macrophages was 3.8-fold higher in SL-HFD mice compared to NL-HFD (P<0.01; Fig 4F). In contrast, the number of CD301+ macrophages was reduced by 40% in the HFD groups (PDiet<0.01), with no additional effect of litter size (Fig 4F). These findings confirmed that the increased number of macrophages observed in the eWAT of SL-HFD mice is attributed to an increased number of M1 macrophages. Consistent with these findings, mRNA expression of pro-inflammatory genes, such as Il6, Tnfa, and Ccl2 (MCP-1) were up-regulated by 4.5 (P<0.05), 3.6 (P<0.05), and 5.1 (P<0.01) times, respectively, in eWAT of SL-HFD compared to NL-HFD mice (Fig 5A). Similar to the P22 animals, Tlr4 expression in SL-HFD was 1.7 times that of NL-HFD (P<0.05; Fig 5A). In addition, Arg1 mRNA expression was 6-fold increased in SL-HFD animals (P<0.01), but surprisingly, Il10 mRNA expression was not different between SL-HFD and NL-HFD mice (Fig 5B). Similarly, circulating concentrations of IL-6, TNF-α, MCP-1, and resistin were 2-, 1.1-, 1.7-, and 3.3-fold increased in HFD animals compared to chow fed mice (PDiet<0.001; Fig 5C). However, there were no additional effects of litter size on these circulating cytokines or resistin (Fig 5C).

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