A GUT-BRAIN NEURAL CIRCUIT CONTROLED BY INTESTINAL GLUCONEOGENESIS IS CRUCIAL IN METABOLIC HEALTH
Résumé
Objectives: Certain nutrients positively regulate energy homeostasis via intestinal
gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient
IGN in glucose control independently of nutritional environment.
Methods: We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the
key enzyme of IGN (I-G6pc-/- mice). We evaluated a number of parameters involved in
energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the
pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic
homeostatic function (leptin sensitivity).
Results: Intestinal-G6pc-/- mice exhibit slight fasting hyperglycaemia and hyperinsulinemia,
glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal
diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from
the basal activation of the sympathetic nervous system (SNS). They are corrected by
treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN,
the homeostatic hypothalamic function (highlighted here through leptin resistance) is a
mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc-/- mice are
corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc-/- mice develop the
hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet.
Conclusions: Intestinal gluconeogenesis is a mandatory function for the healthy neural
control of glucose homeostasis.
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Soty et al Mol Metab 2015.pdf (1.26 Mo)
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