Appetite Regulation

Insulin

-Controversial regarding appetite -Secreted by pancreas in response to elevated blood glucose levels *Anorexigenic*

What does corticotropin-releasing hormone (CRH) do?

-Decreases appetite -Also part of the stress response: it induces anterior pituitary (AP) to release ACTH *Anorexigenic*

What is FTO?

-Fat mass and obesity related protein -α-ketoglutarate-dependent dioxygenase FTO (??) -Physiological FTO encodes an RNA demethylase, but the function of the gene is unknown

Orexigenic hormones/neurotransmitters

-Ghrelin -NPY/AgRP -GABA -MCH -Orexins A & B

The hypothalamus receives input from where?

-Gut -Taste receptors -Other regions

What do orexins A & B do?

-Increase food intake -Increase brown adipose tissue thermogenesis, but increase lipogenesis in white adipose tissue --> increases obesity *Orexigenic*

What does MCH do?

-Increases appetite -Decreases energy expenditure *Orexigenic*

Leptin inhibits _______________ neurons and stimulates ____________ neurons.

-Inhibits NPY/AGRP -Stimulates POMC

Insulin inhibits _______________ neurons and stimulates ________________ neurons.

-Inhibits NPY/AGRP -Stimulates POMC

Anorexigenic hormones/neurotransmitters

-Leptin -Insulin (controversial regarding appetite) -Serotonin -POMC/CART -αMSH -CRF -TRH

What is MC4R? What does it do?

-Melanocortin 4 receptor; G-protein coupled receptor -Activation of MC4R decreases appetite and increases energy expenditure *Mutant protein may stay inside the cell or not respond to the agonist*

Obesity-associated genotypes: Monogenic

-Obesity caused by 1 gene; very rare -Ex: Leptin - secreted by adipose tissue; decreases body weight --Mutations that eliminate leptin result in obesity

The posterior pituitary is an extension of the hypothalamus and secretes ____________________.

-Oxytocin -Vasopressin (=ADH)

What are the three regions of the hypothalamus that are involved in appetite regulation?

-Paraventricular nucleus of the hypothalamus (PVH or PVN depending on which slide. STUPID) -Lateral hypothalamic areas (LHA) -Arcuate nucleus of the hypothalamus (ARC)

Most human traits:

-Polygenic -Affected by environment -Not completely penetrant

What do pro-opiomelanocortin (POMC) neurons do?

-Release α-melanocyte stimulating hormone (α-MSH) *Decreases appetite - anorexigenic*

Ghrelin

-Secreted by the stomach (and duodenum) - Also works other ways (e.g. inhibits the vagus nerve) *Orexigenic*

Leptin

-Secreted from white adipose tissue, levels proportional to body adipose stores -Exerts its effects through the leptin receptor (LEPR) *Anorexigenic*

POMC neurons are stimulated by _____________ and ______________ and inhibited by ____________.

-Stimulated by serotonin and leptin -Inhibited by ghrelin

What does thyrotropin-releasing hormone do?

-Stimulates AP to release thyroid stimulating hormone (TSH). -TSH increases production of TH, which increases energy expenditure. *Anorexigenic*

What does BDNF do?

-Supports growth and maintenance of neurons -Involved in long-term memory via hippocampal neurogenesis -BDNF or TrkB (the BDNF receptor) polymorphisms associated with a wide range of issues

FTO Polymorphism

-The variance that is associated with obesity is in an intron (science don't know why!) 1 allele -> increase 1.2 kg in weight 2 allele -> increase 3 kg in weight; 1.7x rate of obesity

MC4R null mice

-Weighed much more than WT (when fed the same diet, they still weigh more, especially females) -Ate more -Had lower oxygen consumption -Showed no increase in UCP1 (uncoupling protein 1) in brown adipose tissue in response to a leptin injection -> decreased energy expenditure SO ->More energy efficient than WT

The orexigenic pathway

1. Hormone (ghrelin) stimulates NPY/AgRP neurons in the ARC to release GABA, NPY, & AgRP. 2. GABA inhibits the secretion of α-MSH from POMC neurons in the ARC 3. NPY and AgRP stimulate the LHA to secrete MCH, orexin A, & orexin B 4. MCH increases appetite and decreases energy expenditure 5. Orexins increase appetite, increase energy expenditure in brown adipose tissue, & increase lipogenesis in white adipose tissue

The anorexigenic pathway

1. Hormones (leptin or serotonin, maybe insulin) stimulate POMC neurons in the ARC to release α-MSH 2. α-MSH inhibits the secretion of MCH, orexin A, and orexin B from the LHA 3. α-MSH binds to MC4R (receptors) on the PVN 4. PVN releases CRF and TRH 5. CRF decreases appetite; TRH increases energy expenditure

Steps in the search for food

1. Hunger: In the ARC, NPY/AgRP activity is greater than POMC 2. Should I eat?: MCH, Orexin A, & Orexin B are activated in the LHA 3. Hunt and gather food 4. Eat foodz 5. Satiation: meet energy needs; slow and stop eating 6. Stop eating: -CRF is active in the PVN -POMC is again more active in the ARC

Leptin and BDNF pathway

1. Leptin signals POMC neurons to secrete α-MSH 2. α-MSH binds to MC4R (receptors) in PVN and ventromedial hypothalamus 3. MC4R secrete BDNF 4. BDNF (acting through its receptor, TrkB, located on neurons in pretty much all hypothalamic nuclei) signals for *decreased food intake and increased energy expenditure*

Which neurons are in the ARC?

1. Pro-opiomelanocortin - POMC or CART/POMC (CART = cocaine and amphetamine-regulated transcript) 2. Neuropeptide Y/agouti-related peptide - NPY/AgRP

How many human SNPs are associated with obesity?

29 -Severely obese children can be heterozygous for mutations in MC4R --In 80% of these mutations, MC4R stays inside of the cell

What is serotonin?

A neurotransmitter with the same effects on appetite as leptin and insulin *Anorexigenic*

The hypothalamus connects the brain to the "classic" endocrine system and stress via the _______________.

Anterior pituitary gland

MC4R human data

At age 20, most of the carriers of obesity-associated MC4R mutation were obese or very close.

What is BDNF?

Brain derived neurotropic factor

What does Met SNP do in mouse data?

Decreases BDNF in dendrites

___________ increases BDNF.

Exercise -May be the mechanism for exercise-induced increase in cognition

________________________ were used to determine polymorphisms associated with obesity.

Genome-wide association studies

NPY/AgRP neurons are stimulated by ____________.

Ghrelin

In mouse data: What does adult deletion of BDNF do?

Increases body weight due to increased food intake

The PVN and LHA are both _____________ by the ARC.

Innervated

The hypothalamus is part of which system?

Limbic -Limbic system controls emotions

What happens to the leptin pathway when there is less BDNF?

Pathway is decreased -> increased food intake and obesity

What does FTO interact with?

RPGR1P1L and IRX3 (both are involved in brain development) -Mechanism in humans is unclear -FTO null mice are smaller -FTO overexpressing mice are larger

What do NPY/AgRP neurons do?

Release NPY, AgRP, and GABA (GABA is inhibitory) *Increases appetite - orexigenic*

What does the PVN do?

Secretes: -Corticotropin-releasing factor (CRF) -Thyrotropin-releasing hormone (TRH) OR TRF (TRFactor) STUPID

What does the LHA do?

Secretes: -Melanin-concentrating hormone (MCH) -Orexin A & B (hypocretin)

Ghrelin stimulates _______________.

Stimulates NPY/AGRP

Where is FTO expressed?

The ARC

In mice, which protein antagonizes MC4R?

The agouti protein Remember the fat, folate deficient mice? What?

Where is the arcuate nucleus?

The ventral side of the hypothalamus -It has a rich blood supply, so it can sense what is happening outside of the brain easily.

The common BDNF polymorphism is ____________.

pVal66Met (There are 6 other SNPs too) -Decreases the amount of BDNF secreted -Associated with decreased satiety, increased food intake, & increased BMI