Control of appetite

• 1st evidence hypothalamus involved in food intake?

  19th century - Mohr describes a hypothalamic-pituitary injury (bullet in the eye) resulting in obesity

  Babinski-Frohlich syndrome - described first in the early 20th century, tumours in the hypothalamus cause loss of function by compressing it, shown to increase appetite (such that they are never sated) and reduce gonadotropin release, causes obesity and hypogonadism
• Role of POMC/CART neurons in the arcuate nucleus?

  Tonically active, express pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)

  POMC converted to alpha-MSH, stimulates neurons in the PVN with a MC4R (agonist), also project to DMN, LHA, and VMN to decrease food intake when stimulated, increase metabolism via the PVN (TRH)
• Role of NPY/AgRP neurons in the arcuate nucleus

  Tonically active, express neuropeptide Y (NPY) and agouti-related peptide (AgRP)

  AgRP inhibits neurons in the PVN with MC4Rs (endogenous antagonist), NPY activates YR, also project to the DMN, VMN, and LHA (YR) - stimulation increases food intake

  Stimulation of the PVN decreases metabolism (TRH)

  Inhibit oxytocin producing neurons in the PVN (oxytocin administration induces weight loss) - loss of neurons involved in Prader Willi Syndrome
• What is Prader Willi syndrome?

  Rare disorder due to abnormality on 15th chromosome, equal occurrence in males and females and ethnic groups, 1 in 10000-25000 live births

  Causes low muscle tone, short stature (can treat with GH), incomplete sexual development, chronic hunger and downregulated metabolism

  Excessive eating and life-threatening obesity
• Aponte et al 2011 - Landmark study POMC/CART & NPY/AgRP neurons in feeding?

  Selectively stimulated ArcN neurons using optogenetics (channelrhodopsin2) - shows importance in regulation of food intake and metabolic activity

  Showed that NPY/AgRP neuron activation alone promotes food intake - flash light, mouse eats even when not hungry, but only when light on (stops quickly afterwards) - correlation of number of neurons active to food consumed

  POMC stimulation reduces food intake and body weight (act on MC4R receptors - express Ag to block these receptors then no effect of POMC stimulation)
• Overview of how hypothalamic neurons monitor food intake?

  Hormones - originate from adipose tissue, pancreas, GI tract - act on arcuate nucleus

  Nutrients - glucose, free fatty acids, amino acids - act on arcuate nucleus

  Other neurons - Central (NTS, amygdala, OFC, VTA, other hypothalamic nuclei) and peripheral (oropharyngeal, vision, smell, touch) - only the NTS and hypothalamic nuclei act on arcuate nucleus
• Role of Leptin in monitoring food intake?

  Released from adipose tissue, 167 amino acid peptide, circulating levels reflect adipose tissue mass

  Long version of ObR (receptor tyrosine kinase) involved in leptin signalling in the hypothalamus - expressed in POMC/CART (activation stimulates) and NPY/AgRT neurons (activation inhibits)

  Leptin acts to reduce food intake and increase metabolism via the ArcN - long term regulation of food intake and body weight

  Leptin also monitored by neurons in the VMN - KO of ObR either here or ArcN increases obesity, KO of both causes much worse obesity
• Effect of leptin signalling mutations?

  Leptin mutations treated using leptin injections

  Leptin receptor mutations, mutations in the enzyme converting POMC to alpha-MSH, and MC4R mutations account for 5% of cases of childhood obesity - mutations lead to hyperphagia and obesity
• Role of pancreatic hormones in regulating food intake?

  Insulin - released form pancreatic beta cells, circulating levels proportional to body adipose tissue, similar in action centrally to leptin, reduces food intake and increases metabolism - tyrosine kinase receptors on POMC/CART and NPY/AgRP neurons in the ArcNn- binding stimulates POMC, inhibits NPY

  Pancreatic polypeptide (PP) - PP cells in the islets of langerhans release in proportion to calorie intake, binds Y4 receptors in NTS and hypothalamus (ArcN, PVN), may also act via vagus nerve - reduces food intake and increases metabolism
• Effect of GI hormones on food intake?

  Grehlin - Only gastric messenger stimulating food intake, reduces metabolism - plasma concentration rises before meal, falls on feeding (elevated conc in Prader Willi syndrome), receptors on NPY/AgRP neurons, stimulates these neurons, GABAergic inhibition of POMC neurons from the NPY ones

  Peptide tyrosin tyrosin - produced in ileum and colon after food intake, low in fasted state, binds to Y receptors in the ArcN and brainstem to reduce food intake

  Cholecystokinin - increases after meal, high plasma conc decreases meal size but increases meal freq
• Describe how glucose is sensed?

  2 pathways - Glucose metabolism to produce ATP via Glut2, Katp channels etc - depolarise when channels close, and also allosteric modulation of enzymes by glucose

  Can have glucose excited neurons that fire APs to increased glucose (glucose metabolism excites via Katp channels - see using patch clamp, may also be another mechanism), and glucose inhibited cells stop firing APs to increased glucose (unclear how, likely mix of pathways) - unclear if these cells overlap with ArcN feeding neurons

  Glucose sensing neurons also in the LHA, VMN, and NTS
• Role of free fatty acids in feeding control?

  Diffuse across BBB and into cells, esterified to acyl-CoA, modulates conductance of a variety of ion channels (chloride, potassium, calcium)

  May change into phospholipids that are incorporated into membrane to change conductance of ion channels, or used by mitochondria in ATP production
• Role of amino acids in feeding control

  Essential amino acids taken up in diet, so presence reflects food intake

  Leucine selectively activates the mTOR to influence food intake
• Role of leptin in the reward value of food?

  Leptin appears to regulate a certain aspect of food reward, and how much people like an image of food (not for preferences of non-food images)

  Leptin deficient patients like everything, high correlation with liking something and activity in reward regions, correlation vanishes after leptin treatment
• Describe the investigations into choices of natural vs artificial sweeteners

  Humans and mice have strong tendency to prefer natural than artificial (sucrose over sucralose) - give options to mice over range of concs and always prefer sucrose

  Appears to be postingestive rewarding effect after natural that increases DA, not seen for artificial, not based on taste (KO taste receptors and same effect)

  Stimulation of DA reward neurons (optogenetics) when drinking sucralose means prefer artificial - DA release drives preference

  Sucrose > water + DA activation > sucralose
• Describe the role of MCH neurons

  Melanin concentrating hormone neurons - found in the LH, are glucose sensitive (fire when increase in glucose)

  Project to DA reward centres, mediate the nutrient value of sucrose (increased activity increases reward)

  Optogenetic mimicry of glucose sensing by MCH neurons inverts preference for sucrose (increases DA release, increase based on time of activation of MCH neurons)

  MCH neurons required for DA release during sucrose ingestion (show by KO MCH neurons using DTR receptors), and sucrose vs sucralose preference (no preference if KO neurons)