Dr. Labbé completed his postdoctoral studies at University Laval with Dr. Denis Richard on “Brain melanocortin-4 receptor and SNS-mediated brown adipocyte thermogenesis’’ since January 2012.
He completed his master’s degree and doctorate (Ph.D.) in physiology (endocrinology) with Dr. André Carpentier at Sherbrooke’s University (2005-2011) that dealt with the mechanisms associated with ectopic fat deposition in lean tissues during the natural course of type 2 diabetes using positron emission tomography systems.Email Dr Labbe
New article: Loss of hepatic DEPTOR alters the metabolic transition to fasting
- Whole-body DEPTOR KO mice are viable and do not display abnormalities.
- Liver-specific DEPTOR KO mice are hypoglycemic when fasted.
- Loss of DEPTOR promotes mTORC1 and increases oxidative metabolism.
- Rapamycin corrects hypoglycemia in liver-specific DEPTOR KO mice.
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested.
We have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR knockout (KO) mice.
Whole-body DEPTOR KO mice are viable, fertile, normal in size, and do not display any gross physical and metabolic abnormalities. To circumvent possible compensatory mechanisms linked to the early and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a tissue in which DEPTOR protein is expressed and affected in response to mTOR activation. Liver-specific DEPTOR null mice showed a reduction in circulating glucose upon fasting versus control mice. This effect was not associated with change in hepatic gluconeogenesis potential but was linked to a sustained reduction in circulating glucose during insulin tolerance tests. In addition to the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously increased oxidative metabolism in hepatocytes, an effect associated with increased cytochrome c expression but independent of changes in mitochondrial content or in the expression of genes controlling oxidative metabolism. We found that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon fasting, and that acute treatment with rapamycin was sufficient to normalize glycemia in these mice.
We propose a model in which hepatic DEPTOR accelerates the inhibition of mTORC1 during the transition to fasting to adjust metabolism to the nutritional status.
Article: Loss of UCP2 impairs cold-induced non-shivering thermogenesis by promoting a shift toward glucose utilization in brown adipose tissue.
Uncoupling protein 2 (UCP2) was discovered in 1997 and classified as an uncoupling protein largely based on its homology of sequence with UCP1. Since its discovery, the uncoupling function of UCP2 has been questioned and there is yet no consensus on the true function of this protein. UCP2 was first proposed to be a reactive oxygen species (ROS) regulator and an insulin secretion modulator. More recently, it was demonstrated as a regulator of the mitochondrial fatty acid oxidation, which prompted us to investigate its role in the metabolic and thermogenic functions of brown adipose tissue. We first investigated the role of UCP2 in affecting the glycolysis capacity by evaluating the extracellular flux in cells lacking UCP2. We thereafter investigated the role of UCP2 in BAT thermogenesis with positron emission tomography using the metabolic tracers [(11)C]-acetate (metabolic activity), 2-deoxy-2-[(18)F]-fluoro-d-glucose ((18)FDG, glucose uptake) and 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid [(18)FTHA, non-esterified fatty acid (NEFA) uptake]. The effect of the β3-adrenoreceptor (ADRB3) selective agonist, CL316,243 (CL), on BAT (18)FDG and (18)FTHA uptakes, as well as (11)C-acetate activity was assessed in UCP2(KO) and UCP2(WT) mice exposed at room temperature or adapted to cold. Our results suggest that despite the fact that UCP2 does not have the uncoupling potential of UCP1, its contribution to BAT thermogenesis and to the adaptation to cold exposure appears crucial. Notably, we found that the absence of UCP2 promoted a shift toward glucose utilization and increased glycolytic capacity in BAT, which conferred a better oxidative/thermogenic activity/capacity following an acute adrenergic stimulation. However, following cold exposure, a context of high-energy demand, BAT of UCP2(KO) mice failed to adapt and thermogenesis was impaired. We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold.
Caron, A., Labbé, S. M., Carter, S., Roy, M.-C., Lecomte, R., Ricquier, D., et al. (2017). Loss of UCP2 impairs cold-induced non-shivering thermogenesis by promoting a shift toward glucose utilization in brown adipose tissue. Biochimie. http://doi.org/10.1016/j.biochi.2017.01.006