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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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Glucose and insulin tolerance in wild-type and CD1d  mice.High fat fed wild-type (WT, n = 11) and CD1d  (KO, n = 9) mice underwent glucose tolerance tests (GTT) as described in Methods. After 1 week for recovery, all mice underwent insulin tolerance tests (ITT) as described in Methods. Results are presented as the means±SE.
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pone-0019831-g004: Glucose and insulin tolerance in wild-type and CD1d mice.High fat fed wild-type (WT, n = 11) and CD1d (KO, n = 9) mice underwent glucose tolerance tests (GTT) as described in Methods. After 1 week for recovery, all mice underwent insulin tolerance tests (ITT) as described in Methods. Results are presented as the means±SE.

Mentions: We next assessed the effects of NKT deletion on obesity-induced insulin resistance (Figure 4), using insulin (ITT) and glucose tolerance tests (GTT). As Figure 4, Panels A&B show, the GTT and ITT demonstrate that the degree of insulin resistance in obese CD1d−/− mice was similar to obese WT mice. This is also indicated by the area under the curve for the GTT and ITT (Figure 4C and 4D, respectively). Fasting blood glucose concentrations were similar between WT and CD1d−/− mice, as were the fasting insulin concentrations and HOMA values (Figure 5A, B&C). Liver triglyceride levels were also measured and again, no difference between the groups was observed (Figure 5D). Finally, Pyruvate Tolerance Test (Figure 5E) indicated no difference between the two groups.


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)

Glucose and insulin tolerance in wild-type and CD1d  mice.High fat fed wild-type (WT, n = 11) and CD1d  (KO, n = 9) mice underwent glucose tolerance tests (GTT) as described in Methods. After 1 week for recovery, all mice underwent insulin tolerance tests (ITT) as described in Methods. Results are presented as the means±SE.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019831-g004: Glucose and insulin tolerance in wild-type and CD1d mice.High fat fed wild-type (WT, n = 11) and CD1d (KO, n = 9) mice underwent glucose tolerance tests (GTT) as described in Methods. After 1 week for recovery, all mice underwent insulin tolerance tests (ITT) as described in Methods. Results are presented as the means±SE.
Mentions: We next assessed the effects of NKT deletion on obesity-induced insulin resistance (Figure 4), using insulin (ITT) and glucose tolerance tests (GTT). As Figure 4, Panels A&B show, the GTT and ITT demonstrate that the degree of insulin resistance in obese CD1d−/− mice was similar to obese WT mice. This is also indicated by the area under the curve for the GTT and ITT (Figure 4C and 4D, respectively). Fasting blood glucose concentrations were similar between WT and CD1d−/− mice, as were the fasting insulin concentrations and HOMA values (Figure 5A, B&C). Liver triglyceride levels were also measured and again, no difference between the groups was observed (Figure 5D). Finally, Pyruvate Tolerance Test (Figure 5E) indicated no difference between the two groups.

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