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Publication
Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal
gluconeogenesis in hepatic PEPCK-C-knockout mice.
Authors Rahim M, Hasenour CM, Bednarski TK, Hughey CC, Wasserman DH, Young JD
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal JCI insight
Year 2021
Date Published 6/1/2021
Volume : Pages 6 : Not Specified
PubMed Reference 34156032
Abstract The liver is the major source of glucose production during fasting under normal
physiological conditions. However, the kidney may also contribute to maintaining
glucose homeostasis in certain circumstances. To test the ability of the kidney
to compensate for impaired hepatic glucose production in vivo, we developed a
stable isotope approach to simultaneously quantify gluconeogenic and oxidative
metabolic fluxes in the liver and kidney. Hepatic gluconeogenesis from
phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic
phosphoenolpyruvate carboxykinase (PEPCK-C; KO). 2H/13C isotopes were infused in
fasted KO and WT littermate mice, and fluxes were estimated from isotopic
measurements of tissue and plasma metabolites using a multicompartment metabolic
model. Hepatic gluconeogenesis and glucose production were reduced in KO mice,
yet whole-body glucose production and arterial glucose were unaffected. Glucose
homeostasis was maintained by a compensatory rise in renal glucose production
and gluconeogenesis. Renal oxidative metabolic fluxes of KO mice increased to
sustain the energetic and metabolic demands of elevated gluconeogenesis. These
results show the reciprocity of the liver and kidney in maintaining glucose
homeostasis by coordinated regulation of gluconeogenic flux through PEPCK-C.
Combining stable isotopes with mathematical modeling provides a versatile
platform to assess multitissue metabolism in various genetic,
pathophysiological, physiological, and pharmacological settings.




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