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C5a receptor deficiency alters energy utilization and fat storage.

Roy C, Gupta A, Fisette A, Lapointe M, Poursharifi P, Richard D, Lu H, Lu B, Gerard N, Gerard C, Cianflone K - PLoS ONE (2013)

Bottom Line: Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload.Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARγ was increased in muscle and liver.These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Québec, Canada.

ABSTRACT

Objective: To investigate the impact of whole body C5a receptor (C5aR) deficiency on energy metabolism and fat storage.

Design: Male wildtype (WT) and C5aR knockout (C5aRKO) mice were fed a low fat (CHOW) or a high fat high sucrose diet-induced obesity (DIO) diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR.

Results: At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO) as well as smaller gonadal (-38% CHOW, -36% DIO) and inguinal (-29% CHOW, -30% DIO) fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARγ was increased in muscle and liver.

Conclusion: These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

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Related in: MedlinePlus

Evaluation of adipose tissue immune and metabolic function in C5aRKO mice.Gene expression for immune factors CD11c (A) and F4/80 (B) and for lipid-related factors fatty acid transporter (CD36), fatty acid synthase (FAS), lipoprotein lipase (LPL), diacylglycerolacyltransferase-1 (DGAT1), diacylglycerolacyltransferase-2 (DGAT2) and peroxisome-proliferator activated receptor gamma (PPARG) (G) were evaluated in WT CHOW diet (open bars), C5aRKO CHOW (solid bars), WT DIO diet (checkered bars) and C5aRKO DIO (striped bars) in gonadal adipose tissue, where n = 6–12 per group. MCP-1 (C) and KC (D) secretion were measured in ex vivo adipose tissue in WT (white bars) and C5aRKO (diagonally striped bars) mice following overnight (24h) treatment with C5a (50 ng/mL), LPS, or both vs control (CTL) where n = 8–10 per group. Ex vivo C3 secretion (E) and ASP production (F) were measured in media from adipose tissue of WT CHOW diet, C5aRKO CHOW, WT DIO and C5aRKO DIO incubated for 24 h. Results are expressed as means ± SEM; statistical differences were determined by ANOVA followed by Bonferroni post-test, where *P<0.05, **P<0.001 and ***P<0.0001 vs CTL (C, D) or vs WT on their respective diet (A,B,E-G) unless otherwise indicated.
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pone-0062531-g006: Evaluation of adipose tissue immune and metabolic function in C5aRKO mice.Gene expression for immune factors CD11c (A) and F4/80 (B) and for lipid-related factors fatty acid transporter (CD36), fatty acid synthase (FAS), lipoprotein lipase (LPL), diacylglycerolacyltransferase-1 (DGAT1), diacylglycerolacyltransferase-2 (DGAT2) and peroxisome-proliferator activated receptor gamma (PPARG) (G) were evaluated in WT CHOW diet (open bars), C5aRKO CHOW (solid bars), WT DIO diet (checkered bars) and C5aRKO DIO (striped bars) in gonadal adipose tissue, where n = 6–12 per group. MCP-1 (C) and KC (D) secretion were measured in ex vivo adipose tissue in WT (white bars) and C5aRKO (diagonally striped bars) mice following overnight (24h) treatment with C5a (50 ng/mL), LPS, or both vs control (CTL) where n = 8–10 per group. Ex vivo C3 secretion (E) and ASP production (F) were measured in media from adipose tissue of WT CHOW diet, C5aRKO CHOW, WT DIO and C5aRKO DIO incubated for 24 h. Results are expressed as means ± SEM; statistical differences were determined by ANOVA followed by Bonferroni post-test, where *P<0.05, **P<0.001 and ***P<0.0001 vs CTL (C, D) or vs WT on their respective diet (A,B,E-G) unless otherwise indicated.

Mentions: As noted above, C5aRKO mice have smaller adipose tissue depots (Fig 2C and D) and, coupled to the higher C5aR expression level with DIO diet (Fig 3A), this suggests potential alterations in adipose immune function and macrophage infiltration. Accordingly, macrophage markers F4/80 and CD11c were evaluated in adipose tissue. DIO treatment resulted in higher F4/80 (Fig 6A) and CD11c (Fig 6B) expression when compared to the CHOW for both the WT and the C5aRKO, however, the C5aRKO mice on DIO had lower expression vs the WT on DIO. The immune responses of adipose tissue to LPS and C5a were evaluated. In in WT mice, LPS stimulation resulted in an increase in MCP-1 (Fig 6C) and KC (Fig 6D) secretion. In C5aRKO, there is a similar LPS stimulation of both MCP-1 and KC secretion (Fig 6C and D). In adipose tissue from WT mice, while addition of C5a alone had no effect on MCP-1 and KC secretion, C5a has a synergistic effect to LPS. By contrast, in C5aRKO mice there is no C5a effect, and no synergy to the LPS effect.


C5a receptor deficiency alters energy utilization and fat storage.

Roy C, Gupta A, Fisette A, Lapointe M, Poursharifi P, Richard D, Lu H, Lu B, Gerard N, Gerard C, Cianflone K - PLoS ONE (2013)

Evaluation of adipose tissue immune and metabolic function in C5aRKO mice.Gene expression for immune factors CD11c (A) and F4/80 (B) and for lipid-related factors fatty acid transporter (CD36), fatty acid synthase (FAS), lipoprotein lipase (LPL), diacylglycerolacyltransferase-1 (DGAT1), diacylglycerolacyltransferase-2 (DGAT2) and peroxisome-proliferator activated receptor gamma (PPARG) (G) were evaluated in WT CHOW diet (open bars), C5aRKO CHOW (solid bars), WT DIO diet (checkered bars) and C5aRKO DIO (striped bars) in gonadal adipose tissue, where n = 6–12 per group. MCP-1 (C) and KC (D) secretion were measured in ex vivo adipose tissue in WT (white bars) and C5aRKO (diagonally striped bars) mice following overnight (24h) treatment with C5a (50 ng/mL), LPS, or both vs control (CTL) where n = 8–10 per group. Ex vivo C3 secretion (E) and ASP production (F) were measured in media from adipose tissue of WT CHOW diet, C5aRKO CHOW, WT DIO and C5aRKO DIO incubated for 24 h. Results are expressed as means ± SEM; statistical differences were determined by ANOVA followed by Bonferroni post-test, where *P<0.05, **P<0.001 and ***P<0.0001 vs CTL (C, D) or vs WT on their respective diet (A,B,E-G) unless otherwise indicated.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646841&req=5

pone-0062531-g006: Evaluation of adipose tissue immune and metabolic function in C5aRKO mice.Gene expression for immune factors CD11c (A) and F4/80 (B) and for lipid-related factors fatty acid transporter (CD36), fatty acid synthase (FAS), lipoprotein lipase (LPL), diacylglycerolacyltransferase-1 (DGAT1), diacylglycerolacyltransferase-2 (DGAT2) and peroxisome-proliferator activated receptor gamma (PPARG) (G) were evaluated in WT CHOW diet (open bars), C5aRKO CHOW (solid bars), WT DIO diet (checkered bars) and C5aRKO DIO (striped bars) in gonadal adipose tissue, where n = 6–12 per group. MCP-1 (C) and KC (D) secretion were measured in ex vivo adipose tissue in WT (white bars) and C5aRKO (diagonally striped bars) mice following overnight (24h) treatment with C5a (50 ng/mL), LPS, or both vs control (CTL) where n = 8–10 per group. Ex vivo C3 secretion (E) and ASP production (F) were measured in media from adipose tissue of WT CHOW diet, C5aRKO CHOW, WT DIO and C5aRKO DIO incubated for 24 h. Results are expressed as means ± SEM; statistical differences were determined by ANOVA followed by Bonferroni post-test, where *P<0.05, **P<0.001 and ***P<0.0001 vs CTL (C, D) or vs WT on their respective diet (A,B,E-G) unless otherwise indicated.
Mentions: As noted above, C5aRKO mice have smaller adipose tissue depots (Fig 2C and D) and, coupled to the higher C5aR expression level with DIO diet (Fig 3A), this suggests potential alterations in adipose immune function and macrophage infiltration. Accordingly, macrophage markers F4/80 and CD11c were evaluated in adipose tissue. DIO treatment resulted in higher F4/80 (Fig 6A) and CD11c (Fig 6B) expression when compared to the CHOW for both the WT and the C5aRKO, however, the C5aRKO mice on DIO had lower expression vs the WT on DIO. The immune responses of adipose tissue to LPS and C5a were evaluated. In in WT mice, LPS stimulation resulted in an increase in MCP-1 (Fig 6C) and KC (Fig 6D) secretion. In C5aRKO, there is a similar LPS stimulation of both MCP-1 and KC secretion (Fig 6C and D). In adipose tissue from WT mice, while addition of C5a alone had no effect on MCP-1 and KC secretion, C5a has a synergistic effect to LPS. By contrast, in C5aRKO mice there is no C5a effect, and no synergy to the LPS effect.

Bottom Line: Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload.Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARγ was increased in muscle and liver.These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Québec, Canada.

ABSTRACT

Objective: To investigate the impact of whole body C5a receptor (C5aR) deficiency on energy metabolism and fat storage.

Design: Male wildtype (WT) and C5aR knockout (C5aRKO) mice were fed a low fat (CHOW) or a high fat high sucrose diet-induced obesity (DIO) diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR.

Results: At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO) as well as smaller gonadal (-38% CHOW, -36% DIO) and inguinal (-29% CHOW, -30% DIO) fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARγ was increased in muscle and liver.

Conclusion: These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

Show MeSH
Related in: MedlinePlus