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Reg Phys and Pharm > Hormonal Regulation of Appetite and Satiety > Flashcards

Hormonal Regulation of Appetite and Satiety Flashcards

1
Q

Biological factors that influence the oneset of obesity

A

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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2
Q

Health complications associated with obesity

A

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

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3
Q

Why we need fat

A

Energy storage, prevention of starvation, energy reserves

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4
Q

Role of hypothalamus in metabolic homeostasis

A

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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5
Q

Lesion in lateral hypothalamus (hunger centre)

A

Anorexia

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6
Q

Lesion in ventromedial hypothalamus (satiety centre)

A

Obesity

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7
Q

Melanocortins (alpha-MSH) : Anorexigenic

A
  • 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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8
Q

Neuropeptide Y (NPY) : Orexigenic

A
  • 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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9
Q

Agouti-related Protein (AgRP) : Orexigenic

A
  • Co-expresses with NPY in ARC neurons
  • Antagonists to MC3 and MC4 receptors
  • Intracerebroventricular (ICV) AgRP causes long lasting hyperphagia
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10
Q

Leptin (adiposity signal)

A
  • 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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11
Q

Biological roles of leptin

A

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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12
Q

Insulin (adiposity signal)

A
  • 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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13
Q

Animal modes of obesity

A
  • 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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14
Q

Agouti and obesity

A
  • 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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15
Q

Zucker fa/fa (rat)

A

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

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16
Q

db/db (mouse)

A

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

17
Q

Ob/Ob (mouse)

A

Ob: decreases leptin: leads to obesity

18
Q

fat/fat (mouse)

A

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

19
Q

Why are animal models important to human obesity

A

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

20
Q

Genetic causes of human obesity

A
  • 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
21
Q

Leptin therapy in DIO

A
  • 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
22
Q

Two main theories of leptin resistance

A

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

23
Q

Action of Leptin Receptor

A

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
24
Q

Influence of leptin receptor-activated signalling cascades

A

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

25
Q

DIO rodent model

A
  • 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
26
Q

Describe how leptin and insulin display convergent signalling

A
  • 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
27
Q

SOCS3

A
  • 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
28
Q

How does hyperleptinemia contribute to leptin resistance?

A

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

29
Q

How does ER stress contribute to hypothalamic leptin resistance?

A

Decreases leptin sensitivity in the hypothalamus

30
Q

How does inflammation contribute to hypothalamic leptin resistance?

A

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

31
Q

Adiposity signals

A

Released from adipose tissue to regulate food intake

32
Q

Satiety signals

A

Released from the GI tract to regulate food intake

33
Q

Cholecystikinin (CKK)

A
  • 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)
34
Q

Peptide YY

A
  • secreted from endocrine mucosal L-cells of GI tract
  • levels increase rapidly post-prandially
  • inhibits gastric motility, slows emptying and reduces food intake (hypothalamus)
35
Q

Glucagon-like peptide 1 (GLP-1)

A
  • secreted from L cells of GI tract
  • levels increase in response to food ingestion
  • inhibits gastric emptying and reduces food intake (hypothalamus and NTS)
36
Q

Oxyntomodulin (OXM)

A
  • secreted from oxyntic and L-cells of small intestine
  • released after meal
  • suppresses appetite (mechanism site unclear)
37
Q

Obestatin

A
  • secreted from cells lining stomach/SI
  • released in response to ingestion
  • reduces good intake (may antagonise ghrelin)
38
Q

Ghrelin

A
  • 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)

Reg Phys and Pharm (16 decks)

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