Podcast
Questions and Answers
Which of the following peptides is classified as orexigenic?
What is the effect of anorexigenic signals on energy expenditure?
Which neuropeptide is argued not to be a neuropeptide but plays a role in appetite regulation?
What is the primary role of αMSH in the hypothalamus?
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How does fasting affect POMC gene expression?
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Which receptor subtype is primarily associated with melanocortin in the brain?
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What effect do orexigenic signals have on energy storage?
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Which peptide is considered anorexigenic and acts to reduce food intake?
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What role do synthetic agonists play in food intake regulation?
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Which receptor deletion is primarily associated with obesity in mice?
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What is the primary effect of Neuropeptide Y (NPY) when injected into the hypothalamus?
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What type of peptides are predominantly involved in anorexigenic signaling?
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Which substance causes long-lasting hyperphagia when administered intracerebroventricularly?
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What characterizes mice that lack NPY receptor subtypes Y1 or Y5?
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Which of the following is considered to be orexigenic?
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Which neuropeptide is most abundant in the human brain?
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What is the primary function of leptin in the context of energy balance?
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Which of the following accurately describes the source of insulin in the body?
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Which neuropeptide is classified as orexigenic?
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What is a significant effect of neuronal deletion of the leptin receptor (Ob-Rb)?
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What regulatory role does leptin NOT play in the body?
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Which peptide is produced exclusively in the hypothalamus rather than peripheral tissues?
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Which statement about the effects of insulin in the hypothalamus is true?
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Which biological function is primarily associated with leptin?
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Which peptide is primarily produced and secreted by the endocrine mucosal L-cells of the gastrointestinal tract?
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What is the main action of Peptide YY (PYY 3-36)?
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Which orexigenic peptide is NOT classified as a neuropeptide?
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What stimulus leads to the release of Cholecystokinin (CCK)?
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Which of the following statements accurately describes Oxyntomodulin (OXM)?
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Which anorexigenic signal is released from enteroendocrine cells of the duodenum?
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What is the primary function of ghrelin?
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What is the role of obestatin in relation to ghrelin?
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What is the primary role of leptin in energy balance?
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What genetic mutation is responsible for obesity in the db/db mouse model?
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How does the Ay mutation affect obesity in mice?
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What is the biochemistry behind the Zucker fa/fa rat's obesity?
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Which of the following describes the relationship between obesity genes in humans and corresponding mouse models?
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What is the impact of the Ob gene mutation in Ob/Ob mice?
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Which receptor is directly affected by the agouti protein?
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How does fasting influence leptin levels?
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What characterizes the function of CPE (carboxypeptidase E) in obesity?
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What is a significant physiological outcome observed in Ay heterozygotes?
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Study Notes
Hypothalamic regulation - Appetite and Satiety
- Hypothalamus regulates food intake and energy expenditure through short-term and long-term processes
- Short term processes regulate meal initiation, termination and inter-meal frequency
- Long term processes regulate body weight and food intake
Neuropeptides and Obesity
- Hypothalamic regulation of food intake and body weight is influenced by neuropeptides
- Neuropeptides can be produced and released intrinsically in the hypothalamus or produced and secreted peripherally and access hypothalamus
- Orexigenic neuropeptides increase food intake and energy storage and decrease energy expenditure
- Anorexigenic neuropeptides decrease food intake and energy storage and increase energy expenditure
- Examples of orexigenic neuropeptides include NPY, GALANIN, MCH, OREXINS, AGOUTI, GHRELIN, ENDOCANNABINOIDS
- Examples of anorexigenic neuropeptides include LEPTIN, INSULIN, a-MSH, CART, GLP-1, TRH, CRH, PYY3-36
Melanocortins – αMSH
- αMSH (α melanocyte stimulating hormone) is formed by sequential cleavages of the proopiomelanocortin (POMC) precursor polypeptide
- POMC gene expression is reduced on fasting and increased following attainment of a positive energy balance
- αMSH levels are high in the hypothalamus and this peptide inhibits food intake (anorexigenic)
- Melanocortin receptor subtypes MC-3 & MC-4 are mainly expressed in the brain
- Synthetic agonists and antagonists to these receptors suppress and enhance food intake respectively
- Deletion of MC-4 or MC-3 receptor produces obesity in mice
Neuropeptide Y (NPY)
- NPY is a 36 aa peptide and one of the most abundant in the human brain. A significant number of NPY-containing neurons exist in the arcuate nucleus (ARC)
- Injection of NPY into the hypothalamus stimulates food intake and reduces energy expenditure (orexigenic)
- Repeated administration of NPY leads to obesity
- NPY receptor antagonists attenuate feeding and reduce obesity
- Mice lacking NPY receptor subtypes, Y1 or Y5 are pre-disposed to obesity
Agouti-related Protein (AgRP)
- AgRP co-expresses with NPY in ARC neurons
- AgRP and Agouti (Ay) are antagonists to MC3 and MC4 receptors
- Intracerebroventricular (ICV) AgRP causes long-lasting hyperphagia (Orexigenic)
Adiposity signals – Leptin
- Leptin is a member of the cytokine family, 146 aa long, made and secreted from adipocytes
- Leptin circulates in proportion to fat mass (adiposity)
- A specific transport system exists for leptin to enter the brain
- High levels of leptin receptors (Ob-Rb) are expressed on hypothalamic ARC neurons.
- ICV leptin inhibits food intake and decreases body weight of rodents
- Neuron-specific deletion of the leptin receptor (Ob-Rb) results in obesity
Biological Roles of Leptin
- Leptin plays a role in food intake, energy expenditure, fat deposition, peripheral glucose homeostasis, insulin sensitivity, maintenance of the immune system, maintenance of the reproductive system, angiogenesis, tumorigenesis and bone formation.
Adiposity signals – Insulin
- Insulin circulates in proportion to adiposity, although it is secreted from the pancreas
- A transport system for insulin to enter the brain exists
- High levels of insulin receptors are expressed in the hypothalamus, most notably in the ARC
- ICV insulin inhibits food intake and decreases body weight of rodents
- Neuron-specific deletion of the insulin receptor results in obesity
- Peripheral actions of insulin are opposite
Satiety Signals
- Satiety signals are released in response to food ingestion and act to reduce food intake and decrease energy expenditure
- CCK (Cholecystokinin) is released from enteroendocrine cells of the duodenum and jejunum in proportion to lipids and proteins in a meal. It signals via sensory nerves to the hindbrain and directly to the hindbrain (nucleus of solitary tract – NTS)
- PYY 3-36 (Peptide YY) is released from endocrine mucosal L-cells of the G-I tract and increases rapidly postprandially. It inhibits gastric motility, slows emptying and reduces food intake (Hypothalamus)
- GLP-1 (Glucagon-like peptide 1) is released from L-cells of the G-I tract in response to food ingestion. It inhibits gastric emptying and reduces food intake (Hypothalamus and NTS)
- OXM (Oxyntomodulin) is released after the meal from oxyntic and L-cells of the small intestine. It acts to suppress appetite, although the mechanism and site are unclear.
- Obestatin is released in response to ingestion from cells lining the stomach and small intestine. It reduces food intake.
- Ghrelin is an octanoylated peptide produced by oxyntic cells in the stomach. It is a powerful orexigenic peptide that stimulates food intake and decreases fat utilization by acting on the growth hormone secretagogue receptor (GHSR)
Models of Obesity
- Rodent models of obesity are important for elucidating neural pathways of energy balance and play a key role in obesity research
- Monogenic mutations in mouse strains resulting in obesity have been identified and these genes are crucial elements of physiological pathways for energy balance control
- Ob/Ob mouse spontaneously develops obesity through a mutation in the Ob gene, which codes for leptin. Reduced leptin mimics starvation and causes unrestrained appetite.
- db/db mouse spontaneously develops obesity through a mutation in the db gene, which codes for the leptin receptor (Ob-R). The mutation prevents the formation of Ob-Rb, leading to obesity.
- Ay mutation (Agouti yellow) leads to obesity through ubiquitous ectopic expression and acts as an antagonist for hypothalamic MC-4 receptor.
Mouse models of obesity
- Mouse models are used to study the role of different genes in obesity
- In the Zucker fa/fa rat, a mutation in the Ob-R gene results in a dysfunctional leptin receptor, causing obesity and leptin resistance.
- In the db/db mouse, a mutation in the Ob-R gene results in a dysfunctional leptin receptor, causing obesity and leptin resistance.
- In the Ob/Ob mouse, a mutation in the Ob gene causes a deficiency in leptin production, resulting in obesity.
- In the fat/fat mouse, a loss of function mutation in the CPE gene (carboxypeptidase E) results in a deficiency in α-MSH production, leading to obesity.
Rodent mutations in the signalling pathway
- Rodent mutations in genes involved in the leptin-melanocortin signalling pathway are crucial for understanding how the hypothalamus regulates energy balance
- These mutations affect the production and function of key proteins, including leptin, leptin receptor, POMC, AgRP, α-MSH and MC4-R
Parallels between Mouse Models and Humans
- The leptin receptor (Ob-R) gene, POMC gene and MC4-R gene are found in both humans and mice.
- Mutations in these genes can lead to obesity in both humans and mice
Searching for human obesity genes
- Monogenic causes for obesity are rare in humans but are important for understanding the underlying genetic mechanisms.
- Ob mutations are extremely rare in humans.
- Truncated leptin receptor (Ob-R) has been reported in humans.
- Loss of Function POMC mutations are relatively rare, but are present in humans.
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Description
Explore the role of the hypothalamus in regulating appetite and satiety through various neuropeptides. This quiz covers both short-term and long-term processes that influence food intake and energy expenditure. Discover the distinctions between orexigenic and anorexigenic neuropeptides and their impact on body weight.
