Hormonal Regulation of Appetite and Satiety Flashcards
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
Health complications associated with obesity
T2DM, high BP, heart attack, cancers, osteoarthritis, COVID-19
Why we need fat
Energy storage, prevention of starvation, energy reserves
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
Lesion in lateral hypothalamus (hunger centre)
Anorexia
Lesion in ventromedial hypothalamus (satiety centre)
Obesity
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
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
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
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
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
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
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
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)
Zucker fa/fa (rat)
Ob-R gene: decreases functional leptin receptor: leads to obesity and leptin resistance
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)
