Lecture 10: Regulation of Appetite and Obesity

What determines body mass?

• resting metabolic rate

• activity regulated expenditure

• diet induced thermogenesis

• insulin (glucose metabolism)

• GH-IGF1 axis

• thyroid hormone axis

List the process for energy balance.

1. leptin and insulin circulate in the blood in concentrations proportional to body fat content and energy balance

2. leptin and insulin act on central effector pathways in the hypothalamus, repressing brain anabolic neural circuits that stimulate eating and inhibit energy expenditure, while simultaneously activating catabolic circuits that inhibit food intake and increase energy expenditure

3. low leptin and insulin levels in the brain during weight loss increase activity of anabolic neural pathways that stimulate eating and suppress energy expenditure, and decrease activity of catabolic pathways that cause anorexia and weight loss

4. ingestion of food generates neural and hormonal satiety signals to the hindbrain; leptin/insulin-sensitive central effector pathways interact with hindbrain satiety circuits to regulate the meal size, thereby modulating food intake and energy balance

What do anabolic circuits do?

• stimulate feeding

• inhibit energy expenditure

What do catabolic circuits do?

• inhibit food intake

• stimulate energy expenditure

For the appetite/satiety pathway, where do the first and second order neurons reside?

the hypothalamus

What is the first order neuron in the hypothalamus?

arcuate nucleus (ARC)

What does the ARC do?

hunger and satiety sensor

What is the second order neurons in the hypothalamus?

• lateral hypothalamus (LHA)

• ventromedial nucleus (VMN/VMH)

• pareventricular nucleus

What does the LHA do?

hunger center

What does the VMN/VMH do?

satiety center

Which area in the hypothalamus contains receptors to detect hormones circulating in the fed or fasting state?

the ARC

In general, what do the 2nd order neurons do?

detect blood glucose levels

Where does the nucleus tractus solitarii (NTS) reside?

the brainstem

What does the NTS do?

• integrates peripheral information for stretch and hormone signals for feeding and fasting

• sends information to the ARC

Which two neuron populations are present in the ARC for feeding and satiety?

• NPY-AgRP neurons

• POMC neurons

What do NPY/AgRP neurons do?

signal hunger

What do POMC neurons do?

signal satiety

What are the two hormonal signals that regulate ARC neuron activity?

• leptin

• insulin

What does POMC stand for?

pro-opiomelanocortin

What can POMC be cleaved by to form many different peptides?

prohormone convertases

True or False: Prohormone convertases lead to tissue specific cleavages.

true

What type of receptors are POMC peptide receptors?

opioid receptors

What are the POMC peptide receptors in the CNS?

• MC3R

• MC4R

What inhibits MC3R and MC4R?

AgRP

Which pathway does MC4R signal through?

GPCR-G-stimulatory

What does a MC4R deficiency lead to?

obesity

Where does POMC signaling activate MC4R?

the VMH (2nd order neurons)

What does AgRP stand for?

agouti related protein

What is AgRP the inverse agonist at? What does this do?

MC4R; reduces signaling

What does AgRP block the action of?

MSH

What does AgRP induce?

hunger

What do NPY bind to and where?

binds to NPY1R in the hypothalamus

Which pathway does NPY signal through?

GPCR, alpha-inhibitory coupled

What does NPY induce?

hunger

What was the parabiosis experiment used for?

to search for blood born factors

Briefly describe the parabiosis experiments.

• Ob/Ob mouse “cured” by normal mouse

• Db/Db mouse causes normal mouse to starve

• Ob/Ob mouse “cured” by Db/Db mouse

Which condition was the Ob/Ob mice?

no leptin condition

What condition was the Db/Db mice?

no leptin receptor

Briefly describe leptin.

• 167 amino acid peptide hormone

• cytokine

• receptor is LepRb

What does the leptin receptor signal through?

tyrosine kinase, specifically the Jak2 kinase and p-STAT3

True or False: Leptin resistance is similar to insulin resistance.

true

In general, what occurs during leptin resistance?

leptin increases as adipose mass increases, but the brain becomes less sensitive to it

What is specifically occurring during leptin resistance?

• downregulation of receptors

• increase in signaling inhibitors

• less receptor signaling

How can leptin resitance be seen experimentally?

by lowering pSTAT3

True or False: Leptin supplements are not the magic bullet to cure obesity.

true

What does leptin binding lead to?

1. STAT3 phosphorylation

2. pSTAT3 activates POMC

3. POMC represses AgRP

What does leptin and insulin binding lead to?

1. FOX1 phosphorylation

2. FOXO1 leaves nucleus

3. activation of POMC

4. Repression of AgRP

What is FOXO1?

a forkhead transcriptional repressor

What is FOXO1 also involved in?

B-cell dysfunction during Type 2 Diabetes formation

True or False: FOXO1 might be a potential therapy for insulin resistant diabetes and obesity.

true

What type of hormone is ghrelin?

a peptide hormone

What is the receptor for grehlin?

GHSR

What does GHSR stand for?

growth hormone secretagogue receptor

What does ghrelin activity lead to?

direct activation of NPY neurons

True or False: There is a GHSR receptor on NPY neurons.

true

What do PYY, CCK, and GLPs signal?

satiety

What is PPY?

a gut derived satiety signal

What is the receptor for PPY?

NPYR2

What does PPY inhibit?

NPY neurons

What is GLP-1 derived from?

the proglucagon peptide

What is GLP-1?

an intestinal hormone, gut derived satiety signal

What is the receptor for GLP-1?

GLP-1R

True or False: The environment can override the internal homeostatic signals.

true

What are 2 types of in utero exposure that can lead to obesity?

• under/over-nutrition, obesity, and high-fat diet

• exposure to endocrine disruptors

What do in utero exposures lead to? What does this then lead to?

• alteration of epigenome

• cell proliferation

• cell differentiation

• gene expression

• structure

• function

• leads to enhanced appetite and adipogenesis

What did maternal obesity followed by high fat diet in offspring lead to?

• high levels of NPY signaling

• reduced POMC expression

• leptin resistance

What did intrauterine growth restriction lead to?

leptin and insulin resistance

In what ways is development very sensitive to leptin levels?

• neurogenesis

• neural circuit formation

• gene expression (epigenetics)

True or False: Worker bees and queen bees are gentically similar.

true