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Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity.

Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O'Doherty RM - PLoS ONE (2011)

Bottom Line: While the combined genetic deletion of NKT and CD8(+) T-cells improves glucose tolerance and reduces inflammation, interpretation of these data have been complicated by the recent observation that the deletion of CD8(+) T-cells alone reduces obesity-induced inflammation and metabolic dysregulation, leaving the issue of the metabolic effects of NKT cell depletion unresolved.Furthermore, the degree of insulin resistance, glucose intolerance, liver steatosis, and adipose and liver inflammatory marker expression (TNFα, IL-6, IL-10, IFN-γ, MCP-1, MIP1α) induced by high fat feeding in CD1d(-/-) were not different from WT.We conclude that deletion of NKT cells, in the absence of alterations in the CD8(+) T-cell population, is insufficient to protect against the development of the metabolic abnormalities of diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
The contribution of natural killer T (NKT) cells to the pathogenesis of metabolic abnormalities of obesity is controversial. While the combined genetic deletion of NKT and CD8(+) T-cells improves glucose tolerance and reduces inflammation, interpretation of these data have been complicated by the recent observation that the deletion of CD8(+) T-cells alone reduces obesity-induced inflammation and metabolic dysregulation, leaving the issue of the metabolic effects of NKT cell depletion unresolved. To address this question, CD1d mice (CD1d(-/-)), which lack NKT cells but have a full complement of CD8(+) T-cells, and littermate wild type controls (WT) on a pure C57BL/6J background were exposed to a high fat diet, and glucose intolerance, insulin resistance, dyslipidemia, inflammation, and obesity were assessed. Food intake (15.5±4.3 vs 15.3±1.8 kcal/mouse/day), weight gain (21.8±1.8 vs 22.8±1.4 g) and fat mass (18.6±1.9 vs 19.5±2.1 g) were similar in CD1d(-/-) and WT, respectively. As would be expected from these data, metabolic rate (3.0±0.1 vs 2.9±0.2 ml O(2)/g/h) and activity (21.6±4.3 vs 18.5±2.6 beam breaks/min) were unchanged by NKT cell depletion. Furthermore, the degree of insulin resistance, glucose intolerance, liver steatosis, and adipose and liver inflammatory marker expression (TNFα, IL-6, IL-10, IFN-γ, MCP-1, MIP1α) induced by high fat feeding in CD1d(-/-) were not different from WT. We conclude that deletion of NKT cells, in the absence of alterations in the CD8(+) T-cell population, is insufficient to protect against the development of the metabolic abnormalities of diet-induced obesity.

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Alterations in tissue NKT-cell composition in the setting of high fat feeding.Wild-type C57Bl/6 mice were placed on a SCD or HFD for 26 weeks (Panels A and B), 3-weeks (Panel C and D), or 3 weeks followed by a 3-week standard chow diet (Panel C and D). White adipose tissue (WAT), spleen, mesenteric lymph nodes (MLN, only for the 26 week study) and liver were collected from lean and obese mice, immune cells were isolated and underwent FACS, as described in Methods. Results are presented as the means±SE for a minimum of 5 animals in each group. Statistical significance is indicated (*).
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pone-0019831-g001: Alterations in tissue NKT-cell composition in the setting of high fat feeding.Wild-type C57Bl/6 mice were placed on a SCD or HFD for 26 weeks (Panels A and B), 3-weeks (Panel C and D), or 3 weeks followed by a 3-week standard chow diet (Panel C and D). White adipose tissue (WAT), spleen, mesenteric lymph nodes (MLN, only for the 26 week study) and liver were collected from lean and obese mice, immune cells were isolated and underwent FACS, as described in Methods. Results are presented as the means±SE for a minimum of 5 animals in each group. Statistical significance is indicated (*).

Mentions: Previous studies have reported decreases in liver NKT cells in response to a high fat diet. We first sought to confirm and extend these observations, and to assess the effects of diet in other relevant tissues of C57BL/6J mice. In agreement with previous studies [10], [12], [14], there was a selective decrease in the NKT cell population and the NKT activation marker, CD69 in the liver (Figure 1A&B) after exposure to a high fat diet. Conversely, the NKT cell population was enriched in adipose tissue (Figure 1A). NKT populations were not altered in the spleen or mesenteric lymph nodes (MLN). To assess the time-course and reversibility of high fat diet-induced alterations in NKT cells mice were placed on a high fat diet for 3 weeks, and then a proportion of these mice were placed back on a standard chow diet for a further 3 weeks. In response to a 3-week high fat diet, the proportion of NKT cells was reduced to a similar extent as that observed with a prolonged diet. Furthermore, reversion to a standard chow diet for 3 weeks was sufficient to reverse the alterations in NKT cells (Figure 1C). Additionally, there was no change in NKT cell numbers in the spleen at 3 weeks of HFD or when subsequently placed on a standard chow diet for a further 3 weeks (Figure 1D).


Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity.

Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O'Doherty RM - PLoS ONE (2011)

Alterations in tissue NKT-cell composition in the setting of high fat feeding.Wild-type C57Bl/6 mice were placed on a SCD or HFD for 26 weeks (Panels A and B), 3-weeks (Panel C and D), or 3 weeks followed by a 3-week standard chow diet (Panel C and D). White adipose tissue (WAT), spleen, mesenteric lymph nodes (MLN, only for the 26 week study) and liver were collected from lean and obese mice, immune cells were isolated and underwent FACS, as described in Methods. Results are presented as the means±SE for a minimum of 5 animals in each group. Statistical significance is indicated (*).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108591&req=5

pone-0019831-g001: Alterations in tissue NKT-cell composition in the setting of high fat feeding.Wild-type C57Bl/6 mice were placed on a SCD or HFD for 26 weeks (Panels A and B), 3-weeks (Panel C and D), or 3 weeks followed by a 3-week standard chow diet (Panel C and D). White adipose tissue (WAT), spleen, mesenteric lymph nodes (MLN, only for the 26 week study) and liver were collected from lean and obese mice, immune cells were isolated and underwent FACS, as described in Methods. Results are presented as the means±SE for a minimum of 5 animals in each group. Statistical significance is indicated (*).
Mentions: Previous studies have reported decreases in liver NKT cells in response to a high fat diet. We first sought to confirm and extend these observations, and to assess the effects of diet in other relevant tissues of C57BL/6J mice. In agreement with previous studies [10], [12], [14], there was a selective decrease in the NKT cell population and the NKT activation marker, CD69 in the liver (Figure 1A&B) after exposure to a high fat diet. Conversely, the NKT cell population was enriched in adipose tissue (Figure 1A). NKT populations were not altered in the spleen or mesenteric lymph nodes (MLN). To assess the time-course and reversibility of high fat diet-induced alterations in NKT cells mice were placed on a high fat diet for 3 weeks, and then a proportion of these mice were placed back on a standard chow diet for a further 3 weeks. In response to a 3-week high fat diet, the proportion of NKT cells was reduced to a similar extent as that observed with a prolonged diet. Furthermore, reversion to a standard chow diet for 3 weeks was sufficient to reverse the alterations in NKT cells (Figure 1C). Additionally, there was no change in NKT cell numbers in the spleen at 3 weeks of HFD or when subsequently placed on a standard chow diet for a further 3 weeks (Figure 1D).

Bottom Line: While the combined genetic deletion of NKT and CD8(+) T-cells improves glucose tolerance and reduces inflammation, interpretation of these data have been complicated by the recent observation that the deletion of CD8(+) T-cells alone reduces obesity-induced inflammation and metabolic dysregulation, leaving the issue of the metabolic effects of NKT cell depletion unresolved.Furthermore, the degree of insulin resistance, glucose intolerance, liver steatosis, and adipose and liver inflammatory marker expression (TNFα, IL-6, IL-10, IFN-γ, MCP-1, MIP1α) induced by high fat feeding in CD1d(-/-) were not different from WT.We conclude that deletion of NKT cells, in the absence of alterations in the CD8(+) T-cell population, is insufficient to protect against the development of the metabolic abnormalities of diet-induced obesity.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
The contribution of natural killer T (NKT) cells to the pathogenesis of metabolic abnormalities of obesity is controversial. While the combined genetic deletion of NKT and CD8(+) T-cells improves glucose tolerance and reduces inflammation, interpretation of these data have been complicated by the recent observation that the deletion of CD8(+) T-cells alone reduces obesity-induced inflammation and metabolic dysregulation, leaving the issue of the metabolic effects of NKT cell depletion unresolved. To address this question, CD1d mice (CD1d(-/-)), which lack NKT cells but have a full complement of CD8(+) T-cells, and littermate wild type controls (WT) on a pure C57BL/6J background were exposed to a high fat diet, and glucose intolerance, insulin resistance, dyslipidemia, inflammation, and obesity were assessed. Food intake (15.5±4.3 vs 15.3±1.8 kcal/mouse/day), weight gain (21.8±1.8 vs 22.8±1.4 g) and fat mass (18.6±1.9 vs 19.5±2.1 g) were similar in CD1d(-/-) and WT, respectively. As would be expected from these data, metabolic rate (3.0±0.1 vs 2.9±0.2 ml O(2)/g/h) and activity (21.6±4.3 vs 18.5±2.6 beam breaks/min) were unchanged by NKT cell depletion. Furthermore, the degree of insulin resistance, glucose intolerance, liver steatosis, and adipose and liver inflammatory marker expression (TNFα, IL-6, IL-10, IFN-γ, MCP-1, MIP1α) induced by high fat feeding in CD1d(-/-) were not different from WT. We conclude that deletion of NKT cells, in the absence of alterations in the CD8(+) T-cell population, is insufficient to protect against the development of the metabolic abnormalities of diet-induced obesity.

Show MeSH
Related in: MedlinePlus