- small protein, natural antagonist of melanocortin 1 (MC-1) receptor in melanocytes (responsible for hair colour) - mutation results in gene rearrangement causing ubiquitous ectopic expression - Ay mutation leads to obesity - Ay is also antagonist for hypothalamic MC-4-receptor (cause of obesity in mouse model)

Hormonal Regulation of Appetite and Satiety Flashcards by Emma Louise

Biological factors that influence the oneset of obesity

Genetics -> susceptibility genes increase risk of developing disease but are often not essential for disease expression

Environment -> unmask latent tendencies to develop obesity

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Health complications associated with obesity

T2DM, high BP, heart attack, cancers, osteoarthritis, COVID-19

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Why we need fat

Energy storage, prevention of starvation, energy reserves

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Role of hypothalamus in metabolic homeostasis

Integrates signals from the CNS; brain balances weight through orexigenic and anorexigenic pathways, which alter food intake, energy storage, and energy expenditure

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Lesion in lateral hypothalamus (hunger centre)

Anorexia

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Lesion in ventromedial hypothalamus (satiety centre)

Obesity

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Melanocortins (alpha-MSH) : Anorexigenic

Formed by sequential cleavages of the proopiomelanocortin (POMC) precursor polypeptide
POMC gene expression = reduced in fasting
alpha-MSH levels are high in hypothalamus
Receptor subtypes MC-3 and MC-4 are mainly expressed in the brain -> synthetic agonists/antagonists suppress and enhance food intake respectively
Deletion of receptor subtypes produces obesity in mice

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Neuropeptide Y (NPY) : Orexigenic

36 aa peptide
Lots of NPY containing neurons in ARC of hypothalamus
Injection of NPY into hypothalamus stimulates food intake and reduces energy expenditure
Repeated administration = obesity
NPY receptor agonists attenuate feeding, reduce obesity
Mice lacking receptor subtypes Y1 or Y5 are pre-disposed to obesity

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Agouti-related Protein (AgRP) : Orexigenic

Co-expresses with NPY in ARC neurons
Antagonists to MC3 and MC4 receptors
Intracerebroventricular (ICV) AgRP causes long lasting hyperphagia

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Leptin (adiposity signal)

member of cytokine family, secreted from adipocytes
circulates in proportion to fat mass
specific transport system for leptin to enter brain
high levels of leptin receptors (Ob-Rb) expressed on ARC hypothalamic neurons
ICV leptin inhibits food intake and decreases body weight of rodents
neuron-specific deletion of leptin receptor = obesity

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Biological roles of leptin

Food intake/energy expenditure/fat deposition

Peripheral glucose homeostasis/insulin sensitivity

Maintenance of immune system

Maintenance of reproductive system

Angiogenesis (formation of new blood vessels)

Tumorigenesis

Bone formation

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Insulin (adiposity signal)

Ciruclates in proportion to adiposity
Transport system for insulin to enter brain
High levels of insulin receptors expressed in hypothalamus (ARC mostly)
ICV insulin inhibits food intake and decreases body weight of rodents
Neuron-specific deletion of the insulin receptor = obesity
PERIPHERAL ACTIONS ARE OPPOSITE

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Animal modes of obesity

Rodent models of obesity play a key role in elucidating neural pathways
Spontaneous monogenic mutations in mouse strains resulting in obesity

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Agouti and obesity

small protein, natural antagonist of melanocortin 1 (MC-1) receptor in melanocytes (responsible for hair colour)
mutation results in gene rearrangement causing ubiquitous ectopic expression
Ay mutation leads to obesity
Ay is also antagonist for hypothalamic MC-4-receptor (cause of obesity in mouse model)

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Zucker fa/fa (rat)

Ob-R gene: decreases functional leptin receptor: leads to obesity and leptin resistance

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db/db (mouse)

Ob-R gene: decreases functional leptin receptor: leads to obesity and leptin resistance

Ob/Ob (mouse)

Ob: decreases leptin: leads to obesity

fat/fat (mouse)

CPE gene: LoF CPE, decreases alpha-MSH: leads to obesity

Why are animal models important to human obesity

Parallels -> deficiencies in leptin, leptin receptor, POMC or MC4-R led to obesity in both mouse and human

Genetic causes of human obesity

Monogenic causes are rare
Ob mutations are rare - those without detectable leptin are extremely obese
Truncated leptin receptor (Ob-R) reported
LoF POMC (decreases alpha-MSH)
No CPE mutations, mutations in P1 linked to obesity
More common obesity due to MC4R mutations. Most have single mutant allele-reducing signalling
Most human cases of obesity are unknown

Leptin therapy in DIO

vast majority of human diet-induced obesity is characterised by high leptin levels
use of leptin therapeutically is limited by severe leptin resistance present in most obese individuals

Two main theories of leptin resistance

1) defective leptin transport into brain - either mutated or missing
2) altered signal transduction following leptin binding to its receptor - problem is either receptor itself or downstream signalling of receptor

Action of Leptin Receptor

Leptin receptor (Ob-Rb) activates multiple signalling cascades

JAK2-STAT - transcriptional regulation eg SOCS3 and POMC (feeding regulation)
IRS-PI3K - transcriptional regulation and electrical activity of neurons (translational regulation and electrical activity of neurons)
ERK and AMPK

Influence of leptin receptor-activated signalling cascades

Enable leptin to modulate:
- food intake and energy expenditure
- peripheral glucose homeostasis and insulin sensitivity
- immune and reproductive function

DIO rodent model

- closest to human obesity - mice that display resistance to DIO maintain healthy weight - hypothalamic resistance to leptin and insulin in obesity associated with increased hepatic glucose output and peripheral insulin resistance - DIO mice and rats = resistant to peripheral recombinant leptin - evidence indicated DIO individuals are unlikely to respond to leptin treatment

Describe how leptin and insulin display convergent signalling

- both activate PI3K pathway in hypothalamic neurons - inhibition of PI3K prevents leptin and insulin signalling in the ARC - IRS2 knockout displays leptin and insulin resistance (via PI3K pathway) - PTP1B inhibits leptin and insulin pathways and is increased in obesity - PTP1B knockout resistant to DIO and diabetes

SOCS3

- suppressor of cytokine signalling family of intracellular proteins that inhibit JAK-STAT signalling - STAT3 regulating protein that binds to Ob-Rb and prevents leptin signalling - Leptin resistance associated with SOCS3 induction in hypothalamus - SOCS3 increases in rodent models of obesity - suggested mediator of leptin resistance - negative regulator of insulin signalling through IRS

How does hyperleptinemia contribute to leptin resistance?

Driven by high-calorie intake. If there is a decrease in circulating leptin, it restores leptin sensitivity

How does ER stress contribute to hypothalamic leptin resistance?

Decreases leptin sensitivity in the hypothalamus

How does inflammation contribute to hypothalamic leptin resistance?

High calorie intake promotes chronic low-grade neuroinflammation including the hypothalamus -> happens throughout the body in many other organs

Adiposity signals

Released from adipose tissue to regulate food intake

Satiety signals

Released from the GI tract to regulate food intake

Cholecystikinin (CKK)

- secreted from endocrine cells of duodenum and jejumen - released in proportion to lipids and proteins in meal - signals via sensory nerves to hindbrain and stimulates hindbrain directly (nucleus of solitary tract)

Peptide YY

- secreted from endocrine mucosal L-cells of GI tract - levels increase rapidly post-prandially - inhibits gastric motility, slows emptying and reduces food intake (hypothalamus)

Glucagon-like peptide 1 (GLP-1)

- secreted from L cells of GI tract - levels increase in response to food ingestion - inhibits gastric emptying and reduces food intake (hypothalamus and NTS)

Oxyntomodulin (OXM)

- secreted from oxyntic and L-cells of small intestine - released after meal - suppresses appetite (mechanism site unclear)

Obestatin

- secreted from cells lining stomach/SI - released in response to ingestion - reduces good intake (may antagonise ghrelin)

Ghrelin

- secreted from octanoylated peptide, produced by oxyntic cells in stomach - levels increase before and decrease after meals, levels raised by fasting and hypoglycemia - stimulates food intake and decreases fat utilisation by acting on growth hormone secretagogue receptor (GHSR)