Nutrient Sensing in Energy Metabolism (CRUCIANI.pdf) PDF

The role of nutrient sensing in the control of energy metabolism: physiological and pathophysiological overview Céline Cruciani-Guglielmacci, PR Paris 7 CNRS UMR 8251  Energy balance Energy entrance = energy loss  Energy homeostasis Food intake...

The role of nutrient sensing in the control of energy metabolism: physiological and pathophysiological overview Céline Cruciani-Guglielmacci, PR Paris 7 CNRS UMR 8251  Energy balance Energy entrance = energy loss  Energy homeostasis Food intake Resting metabolism Thermogenesis Physical activity In Out Excess of lipids? Lipotoxicity, umbalance sedentarity Obesity, type 2 diabetes The nervous control of energy homeostasis Brain stem Prise alimentaire  A bit of anatomy… Central Nervous System Peripheral Nervous System ENCEPHALUS SOMATIC Brain Interact with environment Hypothalamus Cerebellum Brain stem Nucleus of AUTONOMOUS Solitary Digestion, Breathing, Tract Hormone secretion SPINAL CORD Control of energy homeostasis  Automonous nervous system Sympathetic Nervous System Parasympathetic Nervous System SNS PNS Catecholamines Acetylcholine (NA, A) Catabolic action on Slow down the glucose, lipid and metabolism and drive it protein metabolism to towards energy storage facilitate energy (anabolism) expenditure SNS + PNS are controlling the Enteric Nervous Syst.  Enteric Nervous System GI tract activity  Different hypothalamic nuclei (areas) for the contrôle of energy homeostasis a b Cervelet HT a’ b’ Moelle épinière a b Cx HI TH 3V TH 3V PVN DMH LH LH CO b’ NSC a’ VMH ARC EM ARC (arcuate nucleus) : early access for circulating hormones and nutrients VMH (ventro medial hypothalamus) : « satiety center», activates SNS LH (lateral hyptothalamus) : « feeding center », controls the PNS  For example : nervous VMH LH control of insulin secretion PNS stimulates insulin secretion through Ach Ganglion and muscarinic coeliaque receptors Nerf vague nerf splanchnique Ganglion SNS mainly inhibits parasympathique insulin secretion Rβ Ach NA through noradrenalin RM3 - + R2A and alpha adrenergic receptors Cellule β Sécrétion d’insuline Pancréas endocrine  Signal integration (both nervous and hormonal) in beta cells PNS Insulin secretion SNS  Other organs controlled by ANS SNS PNS Liver  Glycogénolyse  Glycogénogenèse Néoglucogénèse Glycogénogenèse Muscle Utilisation du glucose  Glycogénolyse Activité de la LPL WAT  Utilisation du glucose  Utilisation des AGL Lipolyse Expression de la leptine Activité de la LPL Activité de la LHS Expression de l’ARNm de la leptine BAT Utilisation du glucose Thermogenèse  Expression de l’ARNm de la LPL  And also… Effet de la stimulation Effet de la stimulation Organe cible sympathique parasympathique Diminution de la fréquence, Augmentation de la fréquence et diminution de la force de Cœur de la force de contraction contraction des oreillettes uniquement Dilatation des vaisseaux péniens et Vaisseaux sanguins Constriction clitoridiens Constriction des bronches, sécrétion Poumons Dilatation des bronches de mucus Diminution de la motricité, Augmentation de la motricité, Tube digestif contraction des sphincters, inhibition relaxation des sphincters, stimulation des sécrétions digestives des sécrétions digestives Vessie Relâchement Contraction (évacuation) Dilatation de la pupille (mydriase), Contraction de la pupille (myosis), Œil accommodation pour la vision a accommodation pour la vision de distance près Foie Glycogénolyse Pas d'effet Adipocytes Lipolyse Pas d'effet Pancréas exocrine Inhibition de la sécrétion exocrine Stimulation de la sécrétion exocrine Glandes sudoripares Sécrétion de la plupart de glandes Sécrétion de quelques glandes sécrétion d'un faible volume de Sécrétion d'un grand volume de Glandes salivaires salive, riche en mucus salive, riche en enzymes Sécrétion d'Adrénaline et de Médullosurrénale Pas d'effet Noradrénaline Inhibition de la sécrétion d'insuline, Stimulation de la sécrétion d'insuline Pancréas endocrine stimulation de la sécrétion de et de glucagon glucagon Erection (suite à l'action sur les Organes génitaux Orgasme, éjaculation vaisseaux péniens et clitoridiens) Activité cérébrale Augmentation de la vigilance Pas d'effet Source : Wikipédia  Hypothalamus and brain stem (and others areas?) receive and integrate signals from periphery… Hypothalamus Cervelet Mésencéphale Moëlle épinière Tronc Pont cérébral Bulbe rachidien  Nutrients exert a negative feedback on the CNS (both direct and indirect) DIRECT INDIRECT EFFECTS : EFFECTS: Short term Long term « nutrient sensing » Leptin Insulin CCK GLP1 PYY ghrelin OXM Glucose Lipids (TG, Nerf vague FFA) Adipose tissue Amino acids  The main area of signal integration: the Arcuate Nucleus of hypothalamus NPY/AgRP neurons: Orexigen/Anabolic POMC/CART neuron: Anorexigen/Catabolic POMC/ CART Nutrient sensing D’après Schwartz et al, Nature, 2004. Ghrelin and leptin antagonist action Nutrients arrival in the GI tract : first regulation step Short term CCK GLP1 PYY ghreline OXM Glucose Lipids (TG, Nerf vague FFA) Amino acids Does Your Gut Taste?  FFA uptake and signaling in gut Gastric Fatty Acid 12 C: emptying chylomicrons, inhibition, lymph food intake inhibition FA insulin is not efficient on that group => insulin resistance. CTRL Plasma C peptide 0 8 16 24 32 40 48 (h) (Magnan et al. JCEM 2001) Sécrétion d ’insuline pendant le clamp hyperglycémique Insulin secretion rate (pmol/kg bw/min) Insulin secretion rate were higher in the lipid group. lipides serum (Magnan et al. JCEM 2001)  IL infusion decreases the sympathetic tone If there is less SNS activation -> higher insulin secretion. 1000 0.8 serum 800 0.6 *** lipides 600 *** 0.4 400 0.2 200 0 0 Less SNS inhibition on insulin secretion : hyperinsulinaemia (Magnan et al. JCEM 2001)  In summary, after 48h of high concentration circulating lipids : Insulin resistance Insulin hypersecretion in response to glucose Low sympathetic tone Mimic of « Pre-diabetic state » (IL intravenous infusion : also peripheral effects)  New model : Intracarotid infusion towards brain in rats and mice ? Perfusion centrale IL+hep dans l’artère carotide Central lipotoxicity Système nerveux autonome, ? axe corticotrope… TG infusion ? Circulating FFA and TG concentrations are unchanged Injection of lips inside the brain but WITHOUT changing the circulating FFA and TG conc. That way, they can say if lipotoxicity triggers a change in food intake.  Results after 24h infusion into Perfusion carotid artery : centrale IL+hep dans l’artère carotide  no change in food intake  glycemia, insulinemia and circulating FFA are unchanged (no peripheral effects)  Hyper secretion of insulin in response to glucose Same results than in humans studies. Basal + insuline  due to liver insulin resistance FA are able to enter neurons and are oxydized (beta-ox) inside mitoch. Is Beta oxidation required for mediating lipid effects? Acides Gras Acides gras Acyl-CoA Perfusion icv d’étomoxir: inhibition de la ß oxydation CPT1 ß Oxydation Mitochondrie neurone  ICV infusion of etomoxir into lateral ventricle Results Perfusion centrale IL dans l’artère etomoxir carotide Restauration of hepatic sensitivity. Cruciani-Guglielmacci et al, Diabetologia, 2004  icv etomoxir infusion prevents hepatic insulin resistance Icv etomoxir normalizes GSIS  Yes, Beta oxidation of FAs is a mediator of its deleterious effects… What happens on the ANS during HF diet? Rats submitted to « only » 2 days of HF diet Hypersecretion of insulin in response to glucose  Early change for catecholamine turnover in brain, liver and pancreas. Want to confirm if insulin resistance is due to an decrease in sympathetic tone. The insulinogenic index: a way to modelize insulin efficacy CTRL HF diet  oxymetazoline, an α2 adrenergic agonist, normalizes insulin secretion in response to glucose A lower sympathetic tone is involved in the higher insulin secretion Cruciani-Guglielmacci et al., AJP Endo. Metab, 2004  For example : nervous VMH LH control of insulin secretion PNS stimulates insulin secretion through Ach Ganglion and muscarinic coeliaque receptors Nerf vague nerf splanchnique Ganglion SNS mainly inhibits parasympathique insulin secretion Rβ Ach NA through noradrenalin RM3 - + R2A and alpha adrenergic receptors Cellule β Sécrétion d’insuline Pancréas endocrine What are the molecular pathways implicated in the pathophysiological effects of lipids?  Le neurone sensible aux acides gras Fatty Acids GPR40 GPCR Fatty Acid Transporter Cerulenin Sulfonylurea KATP Channel PKC Fatty Acids PLC DAG Insulin/Leptin LC Acyl-CoA C75 FAS Glucose ATP Etomoxir Malonyl CoA Glucose NO PI3K 2 Bromo- GK palmitate ACC TOFA ATP + CoA G-6-P ATP Acetyl-CoA CPT1 FATP Pyruvate NADH CL AMPK PDH FADH2 AMP + PPi FA Oxidation Fatty Acids Citrate LDH5 PC Acetyl-CoA MC AICAR Leptin Anaplerosis Insulin CS AgRP Glucose Malate OAA Lactate Mitochondria D-3-hydroxybutyrate 4-CIN (Ketones) © Christophe Magnan et Barry Levin Where are fatty acids sensing neurons? Hippocampus is know to be the place for training and memory. Some old studies about brain injuries in the hippocampus area -> some of these people became obese. Proof that hippocampus is involved in the reg of metabolism. Hippocampus and nervous regulation of energy homeostasis  Lipoprotein lipase (LPL) could play a role in FA central detection in the hippocampus ? =>LPL: hydrolyses TGs contained into lipoproteins (VLDL, chylomicrons)  Highly expressed in muscle and adipose tissue in periphery  In brain, LPL is strongly expressed and active in the hippocampus Activité Lpl (Ben Zeev et al, Journal of Lipid Research, 1990) After a meal : decrease in FA and increase in TG. meal TG lipoprotein lipase ? NEFA (FFA) Control of energy homeostasis 77 (From Ruge et al, J Clin Endocrinol Metab 2009) Model of mice deficient in LPL neurons (NEXLPL). Don't only focus in the hypoth -> use the whole brain. NEXLPL-/- : neuron-specific LPL deficiency  Hypothesis: Could the modulation of LPL activity in hippocampus play a role in the nervous control of energy homeostasis? Lpl lox/lox mice injected with an adeno-associated virus expressing Cre-GFP into dorsal hippocampus  Lpl lox/lox mice injected with an adeno-associated virus expressing Cre-GFP into dorsal hippocampus Obesity without hyperphagia…metabolic changes? Unchanged food intake but still fatter mice. Nervous recordings of the ANS PNS is increased in LPL Hip -/- and it favors lower energy expenditure and locomotor activity (anabolism) bc of higher PNS activity. Myriocin, a ceramide synthesis inhibitor, reverses the effects on energy expenditure activity and body weight gain  Decreased LPL activity in hippocampus leads to body weight gain without hyperphagia, through a change in sympatho vagal balance… De novo ceramide synthesis seems to play a key role  Loss of fonction in the hypothalamus Obese phenotype LPL VMH +/+ LPL VMH -/- BW post injection Food intake 45 4,5 ** Food intake by day (g) 40 LPL VMH +/+ 4 Body Weight (g) LPL VMH -/- 35 3,5 30 3 LPL VMH +/+ LPL VMH -/- 25 2,5 20 2 0 5 10 15 1 2 3 4 5 6 7 8 9 10 Weeks Weeks post injection Like in hippocampus, obesity is not the consequence of increased food intake  Lpl loss of function in hypothalamus insulinémie plasmatique (pmol/l) 10 jours 20 LPL VMH +/+ 150 LPL VMH -/- LPL VMH -/- * * LPL VMH+/+ glycémie (mmol/l) * 15 * 100 10 Early glucose 50 intolerance 5 0 0 0 30 60 90 120 0 15 30 minutes minutes 5000 1.1 ** * 4000 Less beam breaks/h RER (VCO2/VO2) 1.0 3000 locomotor 2000 0.9 activity, 0.8 increased 1000 RER : more 0 0.7 fat storage? 7:00 19:00 7:00 7:00 19:00 7:00 LPL VMH +/+ LPL VMH -/- LPL VMH +/+ LPL VMH -/-  LPL gain of function through AAV injection into hypothalamus EE/lean basal BW mCherry 30 * 30 LPL++ kcal/kg lean/h * * 28 ** * 25 26 BW (g) 24 20 22 15 20 0 1 2 3 4 5 6 7 7:00 19:00 7:00 Weeks Less body weight gain Higher energy expenditure Hypothalamic LPL is an essential regulator of energy homeostasis  Also in the striatum and in the hypothalamus… The striatum is the area involved in the reward system, and the motivation to search and « work » for food (also known for its implication in addictive behaviour) Different papers about LPL in the central nervous system Neuronal KO of LPL leads to obesity H.Wang & al., Cell Metab. 2011 Hippocampus Increased body weight Decreased energy LPL expenditure Decreased locomotor activity Accumbens NHypothalamus (Picard et al, Mol Metab, 2014) LPL LPL Increased palatable food preference Hypothalamic deletion of LPL induces obesity and Increased food seeking behavior deregulates glucose homeostasis (Laperrousaz et al. (Cansell et al, Mol Psychiatry, 2014) Diabetologia 2016) S. Luquet Team Hypothalamic LPL controls central thermogenesis Laperrousaz et al. Frontiers in Endocrinology 2018 The take-home message : The nervous system controls both food intake and energy expenditure. Nutrients are not only « energy bricks » but they convey information to the brain. Study of nutrient sensing molecular mechanisms could lead to the discovery of new pharmacological targets …