Serum and cecal metabolic profile of the insulin resistant and dyslipidemic p47^phox knockout mice

Abstract

Involvement of NOX-dependent oxidative stress in the pathophysiology of metabolic disorders as well as in the maintenance of metabolic homeostasis has been demonstrated previously. In the present study, the metabolic profile in p47^phox–/– and WT mice fed on a chow diet was evaluated to assess the role of metabolites in glucose intolerance and dyslipidemia under altered oxidative stress conditions. p47^phox–/– mice displayed glucose intolerance, dyslipidemia, hyperglycemia, insulin resistance (IR), hyperinsulinemia, and altered energy homeostasis without any significant change in gluconeogenesis. The expression of genes involved in lipid synthesis and uptake was enhanced in the liver, adipose tissue, and intestine tissues. Similarly, the expression of genes associated with lipid efflux in the liver and intestine was also enhanced. Enhanced gut permeability, inflammation, and shortening of the gut was evident in p47^phox–/– mice. Circulating levels of pyrimidines, phosphatidylglycerol lipids, and 3-methyl-2-oxindole were augmented, while level of purine was reduced in the serum. Moreover, the cecal metabolome was also altered, as was evident with the increase in indole-3-acetamide, N-acetyl galactosamine, glycocholate, and a decrease in hippurate, indoxyl sulfate, and indigestible sugars (raffinose and melezitose). Treatment of p47^phox–/– mice with pioglitazone, marginally improved glucose intolerance, and dyslipidemia, with an increase in PUFAs (linoleate, docosahexaenoic acid, and arachidonic acid). Overall, the results obtained in p47^phox–/– mice indicate an association of IR and dyslipidemia with altered serum and cecal metabolites (both host and bacterial-derived), implying a critical role of NOX-derived ROS in metabolic homeostasis.

Graphical Abstract

Keywords:

• p47^phox–/– mice
• dyslipidemia
• insulin resistance
• metabolome analysis

Acknowledgements

The support from Prof. Gagandeep Kang (Former Executive Director, THSTI, India) and Dr. Ira Praharaj (Scientist, ICMR Regional Medical Research Centre, Bhubaneswar, India) in helping with the 16S rRNA gene sequencing is gratefully acknowledged. The help and critical inputs of Dr. Manoj Kumar Barthwal (Senior Principal Scientist, CSIR-CDRI, India) during the course of the study are gratefully acknowledged.

Ethical approval

All animal experiments were approved by Institutional Animal Ethics Committee of CSIR-CDRI (IAEC/2014/43) in accordance with CPCSEA guidelines.

Author contributions

HA performed most of the experiments and wrote the manuscript. PP performed a few experiments. SKG and YK performed the metabolomics experiments and analyzed the data. KJ provided the animals and critical suggestions during the study. MD conceptualized the whole project, designed, supervised the studies and has interpreted the data as being presented in the MS; she also edited and finalized the manuscript.

Disclosure statement

The authors declare no competing interests.

Data availability statement

All the data needed to evaluate the conclusions in the paper are provided in the manuscript and/or in the supplementary materials.

Additional information

Funding

The present study was supported by JC Bose National fellowship [SB/SE/JCB-017/2015] and THSTI Core Grant to Madhu Dikshit. Research fellowships to HA from Indian Council of Medical Research and PP from Council of Scientific and Industrial Research, India are acknowledged.