Metabolic and Regulatory Response to Food Intake Lecture

Metabolic and regulatory response to food intake Anand. A. Hardikar, PhD Associate Professor and Head, Diabetes and Islet Biology JDRF Australia T1D Clinical Research Network Fellow (CDA), School of Medicine | Western Sydney University Visiting Professor, Danish Diabetes Academy, Roskilde University...

Metabolic and regulatory response to food intake Anand. A. Hardikar, PhD Associate Professor and Head, Diabetes and Islet Biology JDRF Australia T1D Clinical Research Network Fellow (CDA), School of Medicine | Western Sydney University Visiting Professor, Danish Diabetes Academy, Roskilde University and Steno Diabetes Centre Copenhagen Vice‐President, Islet Society, Sweden www.isletbiology.info | E‐mail: [email protected] @ AnandHardikar COPYRIGHT COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of University of Western Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. Learning objectives 1. Name the hormones involved in the regulation of appetite and know where and under what metabolic conditions they are produced 2. Know the mechanisms of how different hormones lead to increased or decreased food intake 2 Regulation of appetite is a process that involve short‐term regulation, guided by impulses, availability, accessibility and long‐term regulation that is shaped by feeding behaviour and controlled through number of intricate factors. 3 Eating healthy! Australian guide to healthy eating Availability, appearance, preference, odour, palatability of foods Do you know that the diet patch is here??!! https://www.eatforhealth.gov.au/guidelines/australian‐guide‐healthy‐eating 4 Regulation of appetite Data from US Center for Disease control (Washington Post) 5 Obesity susceptibility between individuals is highly genetically determined Genes that influence obesity are mainly expressed in the brain https://www.nature.com/articles/nature14177 6 Factors associated with healthy body weight Priming the reward pathway Likes/dislikes Maternal obesity & diet in pregnancy/lactation (programming) Energy metabolism Long‐term weight CNS Food intake Feeding behavior Genetic factors (short‐term/long‐term) 7 Several systems in the brain are involved in the regulation of feeding Reward & motivation pathway Appetite‐ stimulating neurons High body fat Suppresses appetite and promotes energy expenditure High Leptin Reward system Ventral Tegmental Area (VTA) Accumbens (NA) Nucleus PVN ARC NPY AgRP POMC Appetite‐ suppressing neurons Hypothalamus Ghrelin Activated by Hunger Stimulated by Satiety (Fullness) Brainstem Paraventricular Nucleus (PVN) Arcuate Nucleus (ARC) is the major control centre Neuropeptide Y (NPY) Agouti related peptide (AgRP) Proopiomelanocortin (POMC) 8 Short‐term regulation Hormonal and nutritional signals (circulation) Brainstem Vagus nerve Hypothalamus Low body fat Encourages feeding and energy preservation Long‐term R&M pathway drives food seeking behaviour Gastrointestinal regulators of feeding https://www.nature.com/articles/nature05484 9 Learning objectives 1. Name the hormones involved in the regulation of appetite and know where and under what metabolic conditions they are produced 2. Know the mechanisms of how different hormones lead to increased or decreased food intake 10 Ghrelin (a.k.a the “hunger hormone”) A 28 amino acid peptide hormone released from stomach Produced by P/D1 cells in fundus (& Epsilon cells in pancreas) The pattern of ghrelin release suggests that it governs the feelings of hunger. Although several factors(leptin and gut hormones) reduce food intake, ghrelin is the only known factor to increase appetite through circulation. Central or peripheral administration of acylated ghrelin to rats acutely stimulates food intake & i.v./s.c injection of ghrelin to humans increases feelings of hunger and food intake. Ghrelin regulates glucose hemostasis by inhibiting insulin secretion and regulating gluconeogenesis/glycogenolysis. Ghrelin signalling decreases thermogenesis to regulate energy expenditure. Discovered as an endogenous ligand for growth‐hormone‐secretagogue receptor (GHS‐R) Further reading: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049314/ 11 https://www.nature.com/articles/nature05484 Peptide YY (Peptide tyrosine tyrosine) A 36 amino acid peptide hormone produced by L cells throughout the length of the gut, although it is present at higher concentrations in more distal sections. PYY is released into the circulation after a meal and is reduced by fasting. PYY inhibits gastric motility to delay gastric emptying Acute peripheral administration of PYY3– 36 reduces food intake in rodents and humans. Some individuals have lower fasting and postprandial levels of circulating PYY but others have not found significant differences, suggesting that a reduction in PYY release is unlikely to be involved in the aetiology of obesity. Further reading: https://www.sciencedirect.com/science/article/pii/S01969781 17303364 12 Cholecystokinin A 94 amino acid pro‐peptide hormone produced by enteroendocrine I cells in the intestine Demonstrated in 1928‐1973 as the first gut hormone to influence food intake. Cholecystokinin is released postprandially from the small intestine, and seems to reduce food intake through cholecystokinin 1 (CCK1) receptors on the vagal nerve. CCK secretion is stimulated by ingested fats, proteins, and amino acids, whereas carbohydrates such as glucose cause only a brief, transient increase in circulating CCK levels Aromatic L‐amino acids such as phenylalanine and tryptophan stimulate CCK release through a Ca2+‐dependent mechanism mediated by the calcium‐sensing receptor (CaSR) L‐phenylalanine, L‐leucine, and L‐glutamic acid mediate CCK release through umami taste receptors T1R1 – T1R3 Actions of CCK : Signals or induces satiety Gallbladder contraction Stimulates exocrine pancreatic enzymes for digestion Delays gastric emptying Further reading: https://www.pancreapedia.org/molecules/cholecystokinin 13 Pancreatic polypeptide Synthesized and released from PP cells in the pancreas. Secreted in response to hypoglycemia, ingestion of food, or "sham" feeding (food is chewed, but not swallowed) secondary to vagal nerve stimulation. Secretion is blocked by vagotomy or atropine. Similarly to PYY3–36, it is released after a meal and reduces appetite. Acute peripheral administration to mice and humans reduces food intake and chronic administration reduces body weight in ob/ob obese mice. The food intake and fat mass of transgenic mice overexpressing pancreatic polypeptide are reduced, but such mice also show reduced gastric emptying. However, at present the physiological role of pancreatic polypeptide in energy homeostasis is unknown. Further reading: https://www.sciencedirect.com/science/article/ pii/S0196978106005316?via%3Dihub 14 Amylin (a.k.a. islet amyloid polypeptide) A 37‐residue member of the calcitonin peptide family that is released together with insulin from pancreatic β‐cells in response to food ingestion (Please refer to my previous lecture for actions of insulin & glucagon) Although its main function is thought to be in glucose homeostasis, given peripherally at supraphysiological levels amylin can reduce food intake. Administration of the amylin agonist pramlintide reduces body weight in type 1 and 2 diabetics by ~0.5 and 1.4 kg for up to 1 year [ see Whitehouse, F. et al. Diabetes Care 25, 724–730 (2002) and Ratner, R. et al. Exp. Clin. Endocrinol. Diabetes 113, 199–204 (2005)]. Further reading: https://www.nature.com/articles/ijo200913.pdf and https://www.sciencedirect.com/science/article/pii/S0047637418300459 15 Glucose‐dependent insulinotropic polypeptide (GIP) GIP is a 42‐residue peptide released from K cells in the duodenum after food ingestion. GIP is not reported to have an acute influence on food intake. However, GIP‐receptor‐knockout mice are resistant to obesity when fed a high‐fat diet, Body weight and food intake (and blood glucose) decreased in mice treated with fatty acyl‐GIP (see Cell Metabolism 2021 for further reading: https://www.sciencedirect.com/sci ence/article/pii/S15504131210001 52#! ) 16 Glucagon‐like peptide‐1 (GLP1) Stimulates gut motility, absorption. Does not influence appetite https://www.ncbi.nlm.nih.gov/books/NBK279127/ and check www.glucagon.com (Daniel Drucker’s lab website) 17 …. Glucagon‐like peptide‐1 (GLP1) The same gut endocrine cell type (L cells) that synthesizes PYY also synthesizes GLP1 GLP1 is synthesized as a large precursor protein (preproglucagon), which is processed to produce biologically active 30 amino acid peptide GLP‐1 is released into the circulation after a meal and is a potent incretin — central or peripheral administration strongly stimulates insulin release. Intracerebroventricular administration of GLP‐1 potently reduces food intake in rodents, and peripheral administration of GLP‐1 inhibits appetite in animals and humans. 18 Multiple forms of GLP1 https://www.cell.com/trends/endocrinology‐metabolism/fulltext/S1043‐2760(16)30003‐0 19 Oxyntomodulin Oxyntomodulin is a product of the preproglucagon precursor molecule It is released after a meal. Similar to GLP1, it reduces food intake seems to signal through the GLP‐1 receptor oxyntomodulin does not merely mirror the activities of GLP‐1. Oxyntomodulin has a roughly 50‐fold lower affinity for the GLP‐1 receptor than GLP‐1, but seems to reduce food intake with similar potency. Oxyntomodulin and GLP‐1 might therefore have different roles in energy homeostasis, perhaps mediated by their different pharmacological properties or by tissue‐specific signalling factors. chronic oxyntomodulin treatment causes rats to lose more weight than pair‐fed controls, suggesting that oxyntomodulin increases energy expenditure. Chronic administration of oxyntomodulin can also cause weight loss in humans. In a 4‐week study in which oxyntomodulin or saline were self‐administered by overweight and obese volunteers, the oxyntomodulin‐treated group demonstrated an average weight loss of 0.45 kg per week more than the saline‐treated group. 20 Adiponectin Primarily produced in the adipose tissue, but also in muscle, and even in the brain. Adiponectin plays key roles in regulating appetite and food intake. Altered circulating adiponectin levels have been observed in human eating disorders such as anorexia nervosa, bulimia nervosa or binge eating Adiponectin levels have been used as a (crude) biomarker of insulin sensitivity https://care.diabetesjournals.org/content/26/8/2442 21 Long‐term regulation of feeding Leptin Produced by adipocytes, Signals hypothalamus that fat stores are adequate Zhang et al (1994) 372: 425‐32 (Freidman lab from NY) 22 Why do we like to eat? 1. Fat is an endocrine organ; the largest endocrine organ 2. Leptin ensures long term feeding (even if you fast a day or not) 3. Leptin is a key hormone that comes from fat and goes to your brain, to tell how much energy stores you have. Sadaf Farooqi, Cambridge, UK 23 Leptin deficient children After leptin Before leptin Used functional MRI to look at areas of brain that light up in response to food. https://pubmed.ncbi.nlm.nih.gov/17690262/ https://www.youtube.com/watch?v=YRkl3fbZHiA 24 Leptin therapy for adult obesity? Works in leptin‐deficient obesity Leptin therapy does not work when there is too much of it in the body, but works when there is too little of it. Leptin does not have a negative feedback mechanism (Too much fat too much leptin asking brain to stop eating lean?? Leptins role is to turn on the starvation response. Therefore Leptin deficient individuals show hyperphagia (even ate hospital food!) 25 Melanocortin 4 Receptor (MC4R) 26 Mutations in MC4R is one of the commonest form of monogenic obesity (1% in BMI>30) MC4R pathway can be activated following the release of Leptin Melanocytes (Brown black pigment) Stress(adrenal) Can directly affect feeding pathways in the brain Can affect energy balance by causing lipid breakdown Can be involved in reward pathway for eating Can act on MC4R to promote satiety Can affect insulin action See Giles Yeo/Steve O’Rahily’s work with Labradors 27 Other factors that may relate to influence long‐term feeding 100 trillion Microbial Cells 10 trillion Human Cells 2‐20 million Microbial Genes ~20,000 Human Genes 28 Gut biota and us: Our genomes can be up to 99% identical to the person next to us Yet our guts may share only 10% similarity with the biota between us. We can identify if a person is lean/obese with 90% accuracy using metagenomic sequencing data, but only with 60% accuracy when comparing our whole genomes. 29 Along with the altered lifestyles that contribute to the development of obesity and T2D, we need to think about new (evolved) bugs that may potentially be causal to the increasing epidemic of obesity and T2D, and work towards strategies to counter these. 30 Gut microbiota and obesity Germ‐free mice inoculated with microbiota from obese or lean human twins take on the microbiota characteristics of the donor. Those receiving the obese microbiota (red outline) had an increase in adiposity, whereas those receiving the lean microbiota (blue outline) remained lean Walker AW and Parkhill J, Science 2013 Clemente JC et al (2012) Cell 148 31 031 of 12 Asprosin Aka Wiedemann‐Rautenstrauch syndrome (first described in 1977) Rare autosomal recessive disorder intrauterine growth retardation appear aged at birth, although NPS patients do not show accelerated ageing Congenital partial lipodystrophy, (esp. face and extremities) short stature Hypotonia failure to thrive variable mental impairment death in childhood is common They named the circulating C‐terminal product Asprosin because NPS patients have a white adipose tissue deficiency and WAT appeared to be a source of “Asprosin”. Further reading: https://www.cell.com/fulltext/S0092‐8674(16)30213‐6 32 Is obesity a choice? https://www.youtube.com/watch?v=88tWJ1p5d4o 33 Reward system Direct stimulation of specific brain regions Discovered by James Olds and Peter Milner (1950‐70s) stimulation of the lateral hypothalamus, along with other regions of the brain associated with natural reward, was both rewarding as well as motivation‐inducing Electrical brain stimulation and intracranial drug injections produce robust reward sensation due to a relatively direct activation of the reward circuitry Olds J (1958). "Self‐stimulation of the brain; its use to study local effects of hunger, sex, and drugs". Science. 127 (3294): 315–24. doi:10.1126/science.127.3294.315. “Some rats would perform lever‐pressing at the rates of several thousand times per hour for days” Brain stimulation reward (BSR) does not induce satiety Main currency of reward system is Dopamine Check https://www.youtube.com/watch?v=lEXBxijQREo https://www.youtube.com/watch?v=QX_oy9614HQ 34 Several systems in the brain are involved in the regulation of feeding Reward & motivation pathway Appetite‐ stimulating neurons High body fat Suppresses appetite and promotes energy expenditure High Leptin Reward system Ventral Tegmental Area (VTA) Accumbens (NA) Nucleus PVN ARC NPY AgRP POMC Appetite‐ suppressing neurons Hypothalamus Ghrelin Activated by Hunger Stimulated by Satiety (Fullness) Brainstem Paraventricular Nucleus (PVN) Arcuate Nucleus (ARC) is the major control centre Neuropeptide Y (NPY) Agouti related peptide (AgRP) Proopiomelanocortin (POMC) 35 Short‐term regulation Hormonal and nutritional signals (circulation) Brainstem Vagus nerve Hypothalamus Low body fat Encourages feeding and energy preservation Long‐term R&M pathway drives food seeking behaviour Gastrointestinal regulators of feeding https://www.nature.com/articles/nature05484 36 Useful links Please see links cited throughout the presentation for further reading, esp the following for gut hormones: https://www.nature.com/articles/nature05484 www.glucagon.com (Daniel Drucker’s lab website) and for https://www.youtube.com/watch?v=lEXBxijQREo https://www.youtube.com/watch?v=QX_oy9614HQ Highly recommend watching: https://www.youtube.com/watch?v=88tWJ1p5d4o 37 Thank you! Pass on your comments / feedback on my presentations and feel free to connect back anytime! Anand. A. Hardikar, PhD Associate Professor and Head, Diabetes and Islet Biology JDRF Australia T1D Clinical Research Network Fellow (CDA), School of Medicine | Western Sydney University Visiting Professor, Danish Diabetes Academy, Roskilde University and Steno Diabetes Centre Copenhagen Vice‐President, Islet Society, Sweden www.isletbiology.info | E‐mail: [email protected] @ AnandHardikar 38