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Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status.

Schöttl T, Kappler L, Fromme T, Klingenspor M - Mol Metab (2015)

Bottom Line: Maximal respiration capacity and cell respiratory control ratios were diminished in white adipocytes of each of the four murine obesity models, both in the absence and the presence of impaired glucose tolerance.Limitation was more pronounced in adipocytes of intraabdominal versus subcutaneous fat.Impaired respiratory capacity in white adipocytes solely is not sufficient for the development of systemic glucose intolerance.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nutritional Medicine, Technische Universität München, Else Kröner Fresenius Center for Nutritional Medicine, Freising, Germany.

ABSTRACT

Objective: Several human and rodent obesity studies speculate on a causal link between altered white adipocyte mitochondria in the obese state and changes in glucose homeostasis. We here aimed to dissect whether alterations in white adipocyte mitochondrial respiratory function are a specific phenomenon of obesity or impaired glucose tolerance or both.

Methods: Mature white adipocytes were purified from posterior subcutaneous and intraabdominal epididymal fat of four murine obesity models characterized by either impaired or normal oral glucose tolerance. Bioenergetic profiles, including basal, leak, and maximal respiration, were generated using high-resolution respirometry. Cell respiratory control ratios were calculated to evaluate mitochondrial respiratory function.

Results: Maximal respiration capacity and cell respiratory control ratios were diminished in white adipocytes of each of the four murine obesity models, both in the absence and the presence of impaired glucose tolerance. Limitation was more pronounced in adipocytes of intraabdominal versus subcutaneous fat.

Conclusion: Reduced mitochondrial respiratory capacity in white adipocytes is a hallmark of murine obesity irrespective of the glucose tolerance status. Impaired respiratory capacity in white adipocytes solely is not sufficient for the development of systemic glucose intolerance.

No MeSH data available.


Related in: MedlinePlus

Monogenetic models of obesity: Differences in glucose tolerance but similarities in white adipocyte mitochondrial OXPHOS capacity. (A) Comparison of Lepob/obmice and Lep+/+littermates. Lepob/ob mice show massive obesity and impaired glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–8). (B) Comparison of Mc4RX16/X16and Mc4Rwt/wtlittermates. Mc4RX16/X16 mice show massive obesity but normal glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–9). (A) and (B) Mitochondrial integrity in epididymal white adipocytes is affected in both models as indicated by lowered cell respiratory capacity (cRCR). All data were analyzed by Student's t-test. Bars are presented as means ± SD. p < 0.05, *** = p < 0.001.
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fig8: Monogenetic models of obesity: Differences in glucose tolerance but similarities in white adipocyte mitochondrial OXPHOS capacity. (A) Comparison of Lepob/obmice and Lep+/+littermates. Lepob/ob mice show massive obesity and impaired glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–8). (B) Comparison of Mc4RX16/X16and Mc4Rwt/wtlittermates. Mc4RX16/X16 mice show massive obesity but normal glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–9). (A) and (B) Mitochondrial integrity in epididymal white adipocytes is affected in both models as indicated by lowered cell respiratory capacity (cRCR). All data were analyzed by Student's t-test. Bars are presented as means ± SD. p < 0.05, *** = p < 0.001.

Mentions: Mutant mice of both models were heavily obese (Figure 8A,B; Table 2). Accordingly, posterior subcutaneous and epididymal fat pads were larger compared to wildtype mice (Table 2). Oral glucose tolerance tests revealed impaired glucose tolerance in Lepob/ob mice as indicated by lower glucose clearance and higher total AUC (Figure 8A). In contrast, oral glucose tolerance of Mc4RX16/X16 and Mc4Rwt/wt mice was comparable (Figure 8B). At the same time, plasma insulin of Lepob/ob was more than 5 times higher than plasma insulin of Mc4RX16/X16 mice, indicating better peripheral insulin sensitivity rather than pancreatic compensation as a reason for normalized glucose tolerance in the Mc4RX16/X16 mice (Table 1). Notably, mitochondrial OXPHOS capacity of both mutants, reflected by cRCR, tended to be lower in posterior subcutaneous adipocytes and was massively decreased in epididymal adipocytes (Figure 8A,B).


Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status.

Schöttl T, Kappler L, Fromme T, Klingenspor M - Mol Metab (2015)

Monogenetic models of obesity: Differences in glucose tolerance but similarities in white adipocyte mitochondrial OXPHOS capacity. (A) Comparison of Lepob/obmice and Lep+/+littermates. Lepob/ob mice show massive obesity and impaired glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–8). (B) Comparison of Mc4RX16/X16and Mc4Rwt/wtlittermates. Mc4RX16/X16 mice show massive obesity but normal glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–9). (A) and (B) Mitochondrial integrity in epididymal white adipocytes is affected in both models as indicated by lowered cell respiratory capacity (cRCR). All data were analyzed by Student's t-test. Bars are presented as means ± SD. p < 0.05, *** = p < 0.001.
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fig8: Monogenetic models of obesity: Differences in glucose tolerance but similarities in white adipocyte mitochondrial OXPHOS capacity. (A) Comparison of Lepob/obmice and Lep+/+littermates. Lepob/ob mice show massive obesity and impaired glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–8). (B) Comparison of Mc4RX16/X16and Mc4Rwt/wtlittermates. Mc4RX16/X16 mice show massive obesity but normal glucose tolerance measured by total area-under-the-curve (AUC) (n = 5–9). (A) and (B) Mitochondrial integrity in epididymal white adipocytes is affected in both models as indicated by lowered cell respiratory capacity (cRCR). All data were analyzed by Student's t-test. Bars are presented as means ± SD. p < 0.05, *** = p < 0.001.
Mentions: Mutant mice of both models were heavily obese (Figure 8A,B; Table 2). Accordingly, posterior subcutaneous and epididymal fat pads were larger compared to wildtype mice (Table 2). Oral glucose tolerance tests revealed impaired glucose tolerance in Lepob/ob mice as indicated by lower glucose clearance and higher total AUC (Figure 8A). In contrast, oral glucose tolerance of Mc4RX16/X16 and Mc4Rwt/wt mice was comparable (Figure 8B). At the same time, plasma insulin of Lepob/ob was more than 5 times higher than plasma insulin of Mc4RX16/X16 mice, indicating better peripheral insulin sensitivity rather than pancreatic compensation as a reason for normalized glucose tolerance in the Mc4RX16/X16 mice (Table 1). Notably, mitochondrial OXPHOS capacity of both mutants, reflected by cRCR, tended to be lower in posterior subcutaneous adipocytes and was massively decreased in epididymal adipocytes (Figure 8A,B).

Bottom Line: Maximal respiration capacity and cell respiratory control ratios were diminished in white adipocytes of each of the four murine obesity models, both in the absence and the presence of impaired glucose tolerance.Limitation was more pronounced in adipocytes of intraabdominal versus subcutaneous fat.Impaired respiratory capacity in white adipocytes solely is not sufficient for the development of systemic glucose intolerance.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nutritional Medicine, Technische Universität München, Else Kröner Fresenius Center for Nutritional Medicine, Freising, Germany.

ABSTRACT

Objective: Several human and rodent obesity studies speculate on a causal link between altered white adipocyte mitochondria in the obese state and changes in glucose homeostasis. We here aimed to dissect whether alterations in white adipocyte mitochondrial respiratory function are a specific phenomenon of obesity or impaired glucose tolerance or both.

Methods: Mature white adipocytes were purified from posterior subcutaneous and intraabdominal epididymal fat of four murine obesity models characterized by either impaired or normal oral glucose tolerance. Bioenergetic profiles, including basal, leak, and maximal respiration, were generated using high-resolution respirometry. Cell respiratory control ratios were calculated to evaluate mitochondrial respiratory function.

Results: Maximal respiration capacity and cell respiratory control ratios were diminished in white adipocytes of each of the four murine obesity models, both in the absence and the presence of impaired glucose tolerance. Limitation was more pronounced in adipocytes of intraabdominal versus subcutaneous fat.

Conclusion: Reduced mitochondrial respiratory capacity in white adipocytes is a hallmark of murine obesity irrespective of the glucose tolerance status. Impaired respiratory capacity in white adipocytes solely is not sufficient for the development of systemic glucose intolerance.

No MeSH data available.


Related in: MedlinePlus