week12

• Ghrelin = hunger + growth hormone release
• gastrin = acid secretion in stomach
• insulin promotes glucose uptake in cells to decrease blood glucose. made in pancreatic beta cells.
• glucagon promotes glucose release from cells including glycogenolysis and gluconeogenesis to increase blood sugar levels when hypoglycaemic. made in the pancreatic alpha cells in periods of fasting.
• pancreatic polypeptide (PP) increases gastric motility and signals satiation to the arcuate nucleus
• amylin is used for glucose homeostasis and gastric motility (also pancreas)
• GLP-1 regulates incretin activity and signals satiation to the brainstem and arcuate nucleus from the small intestine
• GLP-2 regulates gastrointestinal motility and growth (from small intestine)
• oxyntomodulin signals satiation and acid secretion (small intestine)
• PYY signals satiation to the arcuate nucleus, from small intestine
• cholecystokinin stimulates gall bladder contraction, gastrointestinal motility, pancreatic exocrine secretion (from duodenum)
• secretin stimulates pancreatic exocrine secretion (duodenum)
• GIP stimulates incretin activity (duodenum)
• motilin stimulates gastrointestinal motility (duodenum0
• ghrelin. 28 amino acid peptide hormone. produced by p/d1 cells in fundus, and epsilon cells in pancreas. only known factor to increaase appetite through circulation. iv/sc injection increases hunger. inhibits insulin secretion and regulates gluconeogensis/glycogenolysis
• Peptide YY is a 36 amino acid peptide produced in L cells in gut. more more distally. post prandial release. reduced by fasting. inhibits gastric motility to delay gastric emptying. reduces food intake
• Cholecystokinin


  94 amino acid pro-peptide hormone produced by enteroendocrine I cells in the intestine
• Cholecystokinin


  • First gut hormone to influence food intake
  • Postprandial release, reduces food intake through CCK1 receptors on the vagal nerve
  • Stimulated by ingested fats, protein and amino acids (carbs = brief)
  • Aromatic l-amino acids (tryptophan) stimulate CCK release through calcium-sensing receptor (CaSR) mechanism
  • L-phenylalaline, l-leucine and l-glutamic acid mediate CCk release through umami taste receptors T1R1-T1R3
  • Induces satiety
  • Contracts gallbladder
  • Stimulates exocrine pancreatic enzymes
  • Delays gastric emptying
• Pancreatic polypeptide (PP) - made by pp cells in pancreas, secreted in response to hypoglycaemia, food ingestion, chewing. secretion blocked by vagotomy or atropine. postprandial release, reduces appetite (so does peripheral administration) --> body weight down. overexpression = less gastric emptying, reduced fat mass + food intake
• Amylin. 37 residue calcitonin peptide. released with insulin from pancreatic beta cells postprandially. peripheral administration can reduce food intake. administration of agonist (pramlintide) reduces body weight in both diabetics by ~0.5-1.4kg for up to one year
• GIP is a 42 residue peptide released from k cells in duodenum postprandially. no acute influence on food intake. GIP-receptor-knockout mice are resistant to obesity on high fat diets. body weight and food intake decreased in mice with excess GIP
• GLP-1 made in L cells. synthesised by preproglucagon. 30 amino acid peptide. strongly stimulates insulin release. short half life, deactivated by DPP-4 cutting off 2 AAs. intracerebroventricular administration potently reduces food intake in rodents. peripheral administration inhibits appetite in animals and humans.
• oxyntomodulin = product of preproglucagon. postprandial release. reduces food intake. signals through GLP-1 receptor. 50-fold lower affinity for GLP-1 receptor, similar potency of effect. potentially increases energy expenditure. (0.45kg/week more loss for patients)
• adiponectin produced in adipose tissue (also muscle + brain). regulates appetite and food intake. release altered by eating disorders. levels used as a crude biomarker of insulin sensitivity.
• adiponectin reduces hepatic glucose output, fat accumulation and inflammation. increases muscular glucose uptake and energy expenditure, inhibits fat accumulation. reduces heart inflammation, endothelial adhesion and foam cell formation.
• adiponectin protects against insulin resistance, T2DM and CAD
• Leptin is produced by adipocytes. signals to hypothalamus that fat stores are adequate. decreases food intake, increases thermogenesis, increases physical activity. fat is the largest endocrine organ. ensures long term feeding.
• leptin therapy works in leptin-deficient obesity. doesn't work with leptin resistance. no negative feedback mechanism. turns on starvation response - hypophagia
• melanocortin 4 receptor (MC4R). mutations = most common cause of obesity (5-6% severe early onset cases). 170 different obesity associated mutations 9~70% heterozygote missense mutations). phenotype - hyperphagia, increased fat + lean mass, increased linear growth, BMI >35kg/mm, T2DM
• MC4R stimulates production of POMC following leptin release. PC1 processes this to produce y-MSH (changes melanocyte colour), ACTH (stress affects feeding pathway), b-lipotropin ( causes lipid breakdown). ACTH processed by PC2 to produce a-MSH (act on MC4R to promote satiety and CLIP (affects insulin action). b-lipotropin processed by PC2 to produce y-lipotropin > b-MSH (low BMR and increased hunger) and b-endorphin (involved in eating reward pathway)
• humans have 10 trillion cells > 100 trillion microbial cells. 20k genes > 20 million microbial genes.
• gut biota influences energy metabolism and feeding responses. identify lean/obese with 90% accuracy using metagenomic sequencing data vs 60% with actual human genome.
• transplanting gut microbiota from lean/fat mouse made other mouse more lean/fat.
• Obesity: firmicutes/bacteroidetes ratio down. bacteroidetes down. methanobrevivacter smithii down. lactobacillus up.
• T2DM: down: firmicutes, clostridia, clostridia coccoides-eubacterium rectale. up: bacteroides-prevotella, betaproteobacteria, bacteroidetes/firmicutes ratio.
• Asprosin is a fasting-induced glucogenic protein hormone. induces hepatic glucose production by using cAMP as a second messenger. elevated with insulin resistance. reduction protects against metabolic-syndrome-associated hyperinsulinism. C-terminal cleavage product of profibrillin. secreted in white adipose tissue. Wiedemann-Rautenstrauch syndrome = rare autosomal recessive disorder. neonatal progeroid syndrome. intrauterine growth retardation. congenital partial lipodystrophy (reduced fat mass). hypotonia (down muscle tone). failure to thrive.
• TAS2R38 gene mutations - yes or no taster for phenylthiocarbamide (PTC). some people don't like bitter vegetables.
• James Olds and Peter Milner (50-70s). discovered stimulation of lateral hypothalamus, and other natural reward areas = rewarding + motivation inducing. brain stimulation reward (BSR) doesn't induce satiety. main reward currency is dopamine.
• 280 aus every day develop T2DM. >120k in past year. fastest growing chronic disease. 1.4 million diagnosed cases, up to 500k estimated silent. 3.3 million by 2031.
• T2DM 6th leading cause of death, >$10 billion annual financial cost. Indigenous 3x more likely. 12% in 2004-5. 55-64yo proportion to diabetes deaths 4x greater than non-ind.