Endocrine Control of Food Intake Flashcards
Leptin:
- a. Circulates at levels proportional to the nutritional value of the stomach contents
- b. Inhibits the hypothalamo-pituitary gonadal axis
- c. Resistance prevents its use as an anti-obesity agent
- d. Circulates at levels that positively correlate with body mass index
- e. Circulating levels are increased by loss of adipose tissue
- False
- False
- True
- True
- False
Response Feedback: It circulates at levels proportional to white adipose tissue It has a permissive effect on the hypothalamo-pituityary-gonadal axis Circulating leptin levels fall with a loss of white adipose tissue
Regarding the central regulation of food intake:
- a. Neuropeptide Y-expressing neurons inhibit food intake
- b. Dysfunctional mutations in the gene encoding neuropeptide Y have been shown to result in obesity
- c. Pro-opiomelanocortin is post-translationally processed to form agouti-related peptide
- d. Pro-opiomelanocortin neuronal cell bodies are located in the hypothalamic paraventricular nucleus
- e. Alpha-melanocyte stimulating hormone acts as an endogenous agonist of the melanocortin-4 receptor
- False
- False
- False
- False
- True
Response Feedback: NPY increases food intake No mutations in the NPY gene have been identified. Since NPY increases food intake, one would expect that a mutation in the NPY gene would cause a decrease rather than increase in food intake and hence body weight POMC is post-translationally processed to form alpha MSH POMC neuronal cell bodies are located in the hypothalamic arcuate nucleus with neuronal projections to the PVN
Regarding gastrointestinal hormones:
- a. Ghrelin stimulates the activity of pro-opiomelanocortin neurons
- b. The primary source of circulating glucagon-like peptide-1 is the pancreas
- c. Ghrelin release is increased by fasting
- d. Ghrelin stimulates glucose-stimulated insulin release
- e. Glucagon-like peptide-1 release is stimulated by the presence of nutrients in the gut
False False True False True Response Feedback: Ghrelin increases food intake and activates orexigenic AGRP rather than anorectic POMC neurons. Glucagon and GLP-1 are both products of the preproglucagon gene. Glucagon is produced in the pancreas and GLP-1 is produced by L cells in the gut. GLP-1 rather than ghrelin stimulates glucose-stimulated insulin release.
What is body weight homeostasis a balance of?
Food intake
Energy expenditure
Describe the location of the important nuclei involved in appetite?
In hypothalamus;
Arcuate nucleus and paraventircular nucleus
What enables hormones to communicate easily with the hypothalamus? What is the function of the hypothalamus?
Incomplete BBB —> access to peripheral hormones.
Integrates peripheral and central feeding signals.
What are the two neuronal populations found in the arcuate nucleus? What are their functions?
- NPY/Agrp neurons – stimulate appetite
- POMC neurons – inhibit appetite
Both sets of neurons extend to other hypothalamic and extra-hypothalamic regions
Describe how the neuronal populations of the arcuate nucleus regulate appetite.
Stimulation of MC4R decreases food intake:
- POMC is cleaved to release alpha-MSH,which then binds and activates the MC4R to inhibit food intake
- Agrp neurons inhibit the MC4R receptor so food intake is increased
What is the result of POMC deficiency or MC4-R mutation?
MC4-R mutation/POMC deficiency –> morbid obesity
POMC deficiency also results in ginger hair
MC4R function is to reduce food intake so if you have an abnormality in this signalling pathway then you can’t suppress food intake
Are there any mutations of Agrp or NPY associated with appetite?
None found in humans so far
Describe the ob/ob mouse experiment.
Ob gene recessive mutation caused:
- Profound obesity
- Hyperphagia = can’t stop eating
- Diabetes (because of the food intake)
- Decreased body temperature
- Decreased energy expenditure
Why was the ob/ob mouse obese?
Recessive mutation in the ob gene —> no leptin production because Ob gene codes for leptin.
Where does leptin come from? Where does it act?
White adipose tissue
Hypothalamus has Ob-R receptors
Describe leptin signaling.
- Low leptin when low body fat
- High leptin when high body fat
Activates POMC neurons which release alpha-MSH and inhibits the opposite NPY/AgRP neurons so causes suppression of appetite through MCR4
What happens when you inject leptin into someone? Despite this why is it not a good anti-obesity drug?
Central/peripheral administration of leptin à decreased food intake and increased thermogenesis
- It circulates in plasma proportional to fat
- Obese humans already have high leptin
- MOST obesity causes LEPTIN RESISTANCE in the brain– hormone no longer signals properly even though it is present. —> SO leptin is ineffective as a weight loss drug
When is leptin still effective as a treatment? Why does its efficacy decrease with use?
In patients with Ob gene mutation causing a lack of leptin
- These individuals are morbidly obese but drop weight once leptin injections are given every day
- BUT it is a peptide so you can develop antibodies against it so you need to keep increasing the dose*
What can help you tell when a child has a leptin deficiency?
Centile charts
What is the role of insulin in food intake?
- It circulates at levels proportional to body fat
- Receptors in hypothalamus and central administration of insulin leads to reduced food intake
Traditionally we thought of insulin as just a hormone which reduces blood glucose but it might also be working through the arcuate nucleus to reduce food intake
What determines the levels of insulin in our bodies?
Insulin ciruclates at levels proportional to body fat
What are the endocrine cells of the gut called? How many hormones can they secrete?
- Enteroendocrine cells or L cells
- Releases more than 20 different regulatory peptide hormones.
What is the function of gut hormones? How is their release regulated?
- Gut motility
- Secretion of other hormones
- Appetite
Release regulated by gut nutrient content.
Where is ghrelin released? When is it released?
- In the stomach
- It is a “hunger hormone” – released just before meals and drops after.
Describe ghrelin signaling. (What happens when you give someone an injection of ghrelin compared to saline before a meal?)
- Modulates neurons in the arcuate nucleus –> stimulates NPY/Agrp neurons
- Inhibits POMC neurons
- So net effect is increases appetite
(Food intake will be greater after an injection of ghrelin)
Which peptide has the opposite effect to ghrelin?
Peptide YY (PYY) = satiety hormone, makes you feel full and is highest when you have ate a lot.
When are PYY levels highest? Describe PYY signalling.
After a bigger meal
- Inhibits NPY release from NPY/Agrp neurons
- Stimulates POMC neurons
- Decreases appetite
What is the gene coding for GLP-1? When is GLP-1 released?
Preproglucagon gene
Released after eating – post prandially - from enteroendocrine cells of the gut
What type of hormone is GLP-1 and what is its function?
Incretin = a hormone that is released after eating and augments insulin secretion from beta islet cells
Its incretin role also reduces food intake.
Give examples of 2 incretin-based therapies approved for use in diabetes.
GLP-1 agonists = injectable only; mimic the effects of GLP-1
DPP-4 inhibitors = oral tablets; DPP-4 causes breakdown of GLP-1 so this inhibitor prolongs GLP-1 effects.
Why can GLP-1 not be directly injected in its active form as a treatment for diabetes? How has this been overcome?
It has a very short half-life - 1min
So an inactive form has been produced - Saxenda
What is Saxenda? Describe its uses.
Long-acting GLP-1 receptor agonist (liraglutide) from Novo Nordisk.
Double the dose used for T2DM - helps with weight loss too
What are the problems with using PYY3-36 as a drug?
- Narrow therapeutic window
- Above certain plasma levels it induces nausea and vomiting.
List some comorbidities associated with obesity.
How do we know that there is a genetic influence on obesity?
Monozygotic and dizygotic twin studies:
Monozygotic twins, whether raised together or apart will maintain similar body mass in reponse to controlled overfeeding. There is less intrapair correlation in dizygotic twins. This shows there is a strong genetic influence on body mass and adiposity in humans.
What is the thrifty gene hypothesis? What is the evidence for it?
- There are specific genes which were selected for to increase metabolic efficiency and fat storage in the past.
- Today, in the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes
_Evidence_: Populations historically prone to starvation become most obese when exposed to Western diet and sedentary life-style (e.g. Pima Indians, Pacific Islanders).
What is the adaptive drift (drifty gene) hypothesis?
Normal distribution of body weight: the fat are eaten, the thin starve so most people ended up in the middle BUT when humans learned to defend against predators the n obesity was not selected against
In current context, the inheritors of these genes become obese.
Image shows: Some people have susceptibility genes to e.g. obesity but will not manifest the disease phenotype in a healthy environment. When put in a toxic environment the phenotype will manifest in the prone and not in the genetically resistant population.
