The global pandemic of obesity and Type 2 Diabetes (T2DM) is a major health problem. According to the WHO, the number of deaths from obesity and T2DM will double between 2005 and 2030. The urgent need to identify new treatments without side effects therefore remains increasingly relevant and new therapeutic strategies must be developed. Obesity and T2DM are associated with resistance to the action of insulin in its target tissues (muscle, liver, adipose tissue…) and with alterations in the metabolism of carbohydrates and lipids. An increase in lipid intake and/or a reduction in mitochondrial oxidation of fatty acids (FAO) in the liver and skeletal muscle participate in the development of insulin resistance. When the intake of long-chain fatty acids (LCFAs) exceeds the oxidative capacity of the cell, the accumulation of toxic lipid derivatives interferes with insulin signaling, and are associated with insulin resistance, oxidative stress and inflammation.

Carnitine palmitoyltransferase 1 (CPT1) is a key regulatory enzyme that controls the mitochondrial entry of LCFA. Its activity is inhibited by malonyl-CoA, a metabolic intermediate of de novo LCFA synthesis (lipogenesis). This CPT1/malonyl-CoA partnership is considered as a « fuel sensor » regulating the rate of FAO according to the relative disposal of LCFA and glucose. Our research aims to better understand the pathophysiological importance of CPT1/malonyl-CoA partnership in different organs, tissues or cells, as well as the alterations of the carbohydrate-lipid metabolism in various pathological situations. Other projects are being developed in close collaboration with laboratories given our expertise in the exploration of metabolic fluxes using radiolabeled tracers and of mitochondrial function, in particular by High-Resolution Respirometry.

Mitochondrial lipid oxidation and metabolic diseases (funded by IDEX 2015-2017, SFD  2014, SFD 2017-2021)

We showed that expression of a constitutively active form of CPT1 (CPT1mt) in adult mouse liver (Monsénégo et al. J. Hepatol. 2012) or muscle (Vavrova et al. Am. J. Physiol. 2016) increased FAO capacity of the targeted tissue, and decreased diet-induced tissue lipotoxicity and insulin resistance in vivo. Muscle CPT1mt expression also induced muscle remodeling towards an oxidative phenotype mimicking physical exercise (Hénique et al. FASEB J. 2015). This provided evidence for the pathophysiological importance of controlling mitochondrial fatty acid entry in metabolic diseases (PhDs of J. Monsénégo, C. Hénique and E. Vavrova).

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue and is the liver manifestation of the metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is the major complication of NAFLD as it has potential risk of progression towards cirrhosis and hepatic carcinoma. Clinical or biological parameters cannot presently predict the patients’ histological lesions. Moreover, altered hepatic mitochondria or oxidative phosphorylation defects are typically observed during NASH but the precise role of mitochondria in NAFLD remains poorly understood. In close collaboration with clinicians from Jean Verdier Hospital (Bondy), we examined the interrelations between FAO, mitochondrial bioenergetics and liver status (normal, steatosis or NASH) in fresh liver biopsies from morbidly obese patients undergoing bariatric surgery. Our main results showed that LCFA metabolic orientation (esterification/ FAO) is not affected by the liver status, but the presence of NASH correlates with impaired complete FAO and mitochondrial respiration (PhD of  N. Helmy, MD surgeon ; Masrer2 of G. Phillouze, MD surgeon).