Neuroendocrine Regulation of Metabolism Flashcards
1
Q
Energy balance
A
Energy intake = energy expenditure
2
Q
Where do we get energy from?
A
foods and beverages consumption
3
Q
Hunger
A
- Physiological drive to eat
- Controlled by the body
- Opposite of hunger is satiety
4
Q
Appetite
A
- Psychological drive to eat (external)
- Appetitive behavior
5
Q
How do we use or release energy?
A
- BMR
- Thermic effect of food (TEF)
- Physical activity
6
Q
What is the role of reward centers in energy?
A
- Food consumption is rewarding (increase palatability)
- Regulate food motivation and preferences
7
Q
What is the role of the hypothalamus in energy?
A
- Receives info via circulation hormones on available energy storage
- Gut innervating neurons project directly to the hypothalamus, mainly to the arcuate (ARC) neurons
- Anorexigenic (stops eating, ventromedial) and orexigenic centers (eats, lateral)
8
Q
What is the role of the gut-brain axis in energy?
A
- Signals released from the GI tract monitoring nutrients
- Info conveyed by the vagus nerve to the NTS (brainstem)
9
Q
Short-term regulation of intake
A
- Peripheral
- Within meal-to-meal basis
- Info conveyed via nerve
- Determines the quantity and quality of food eaten during meals/days
10
Q
Long-term regulation of intake
A
- Central
- From days to weeks
- Information conveyed circulating hormones
- Set the tone (modulates short term signals, sensitivity, BMR)
11
Q
Arcuate Nuclears
A
- ARC is closed to the third ventricle
- Responds to circulating signals (leptin)
- Contains two populations of neurons (first-order neurons):
1. POMC/CART
2. NPY (neuropeptide Y) / AgRP (Agouti gene-related protein) - NPY neurons have a GABAergic inhibitory action on POMC neurons
12
Q
How do first-order neurons project to the hypothalamus?
A
- Second order neurons in the PVN (hypothalamus)
- PVN is the satiety center
- PVN neurons can secrete anorexigenic NTs such as:
1. Corticotropin releasing factor (CRF)
2. Thyrotropin-releasing hormone (TRH)
3. Oxytocin - MC4-R activation by alpha-MSH stimulates CRF, TRH, and oxytocin release
- AgRP is a melanocortin agonist
- NPY binding to Y1R inhibits CRF, TRH, and oxytocin release
- Melanocortin signaling: balance between alpha-MSH and melanocortin antagonist AgRP at the MC4R receptor
13
Q
How do first-order neurons project to the lateral hypothalamic area (LHA)?
A
- NPY/AgRP neurons project to the LHA
- LHA is a hunger center
- LHA neurons secrete orexigenic peptides (Orexin-A and MCH)
- Y1R activation stimulates LHA neurons
14
Q
Leptin Signaling
A
- 16kDA hormone secreted by adipocytes, proportionally to fat mass
- Feedback signal on available energy storage in adipose tissue
- Levels decreases with fasting
- Circulating leptin enter the brain in proportion to its plasma levels
- Long form of the receptor (Ob-R: leptin receptor) serves as a transporter
- Leptin reduces appetite
- Leptin regulates POMC
- Leptin acts at the level of the ARC
15
Q
Explain the Leptin signaling pathway (receptor).
A
- Leptin binds to the receptor (dimer)
- JAK2 phosphorylation (both sides)
- Phosphorylation of STAT3
- Phosphorylated STAT3 are released from receptor and move to nucleus together
- Transcription of genes (ex: POMC)
- SOCS3 inhibits JAK2 phosphorylation
- Box 1: JAK2 recruitment
- Box 2: STAT3 recruitment
16
Q
How does leptin impact POMC neurons?
A
- Activates POMC neurons by direct depolarization
- Increases POMC transduction
- Increases alpha-MSH release
17
Q
How does leptin impact NPY/AgRP neurons?
A
- Inhibits NPY/AgRP neurons via hyperpolarization
- Decreases expression of neuropeptides
- Decreases releasing activity
- Decreases inhibitory feedback onto POMC/CART neurons
18
Q
How does leptic impact energy expenditure?
A
- Modulates activity
- Thermogenesis
19
Q
Insulin Signaling
A
- Insulin secreted by pancreatic beta-cells
- Carbs and protein consumption stimulate insulin secretion
- Insulin release increases with body mass
- Levels decrease with fasting
- Insulin enters the brain proportionally to its circulating concentration by an IR-mediated mechanism (tyrosine kinase)
- Transport into the brain can take hours following increase in circulating levels
- Insulin stimulates anorexigenic neurons
20
Q
Insulin Receptor Function
A
- Insulin binds to receptor (dimer)
- Phosphorylation of IRS1
- Phosphorylation of PI3
- Phosphorylation of AKT
- Glucose transport, glucose utilization, neoglucogenesis
- SOCS3: inhibits IRS1 phosphorylation
21
Q
Adipokine or Adipocytokines
A
- Cytokines secreted by the adipose tissue (leptin, adiponectin)
22
Q
Adiponectin
A
- Protein hormone (244-AA long)
- High circulating levels
- Acts via activation of GPCR (AdipoR1 and AdipoR2)
- Participates in control of glucose and lipid metabolism
- Increases tissue sensitivity to insulin= incretin
23
Q
Obesity
A
- Disease: eating continues beyond satiety
- Inflammation: normal body first response directed towards containment or elimination of microbial invaders (component of the innate/nonspecific immunity)
- Cellular and humoral responses
- As body weight increases, circulating leptin levels rise (high intake is maintained and no changes in energy expenditure are detected
24
Q
Acute Inflammatory Response
A
- Series of tissue responses that occurred within the first few hours following injury (redness, heat, swelling, pain, loss of function)
- Strong response that gradually declined until offending agent is undetectable
25
Q
Regulation of the inflammatory response
A
- Resolution of inflammation is an active process
- Several anti-inflammatory factors are being released during an acute inflammatory response
26
Q
Chronic inflammation
A
- Response to persisting inflammatory triggers
- Inflammation is a factor of pathologies and metabolic abnormalities associated with obesity (type 2 diabetes, atherosclerosis, CVD)
27
Q
Leptin resistance
A
- Central leptin resistance developed
- ARC neurons do not respond to leptin anymore
- Leptin signals via induction of STAT3
- SOCS3 is part of negative feedback loop regulating STAT3
- SOCS3 blocks leptin signaling
- When leptin levels rise, SOCS3 protein levels increase
- Inflammation also induces SOCS3
- Block leptin signaling
- Transport to brain also altered
28
Q
Ob/ob and db/db receptors
A
- Lacking leptin receptors
- Ob: lacking leptin
- Db: lacking receptor
- Hyperphagia in ob/ob mice and Zucker rat is due to an increase in meal size
29
Q
MC4R
A
- MC4R KO mice are hyperphagic and obese
- Animals eat larger meals and have increase preference for fats
30
Q
Y1 agonist versus antagonist
A
- Y1 agonist: increase in meal size
- Y1 antagonist: reduces food intake
31
Q
Monogenic Obesity
A
- Leptin-melanocortin pathways
- Leptin deficiency (Ob/Ob) is a rare recessive genetic disorder
- Leads to: hyperphagia, food seeking behavior, aggressive behavior when food restricted
32
Q
Effects of leptin therpy.
A
- Reduced overall energy intake
- Decreased meal size
- Decreased motivation to eat
33
Q
Mutations in MC4R
A
- More common than LEP
- 2-3% of childhood and adult obesity cases
- Hyperphagia
- Complete or partial loss of function
34
Q
Loss of POMC
A
- Results in: hypothyroidism, obesity, loss of hair pigmentation
- Use of MC4R agonist was inefficient in impacting weight and. intake
- Other mutations include beta-MSH, PC1 (POMC maturation)
35
Q
Prader-Willi Syndrome
A
- 1 in 10,000 to 30,000 people worldwide
- Loss of function of genes on chromosome 15
- Segment of paternal gene is deleted
- Hypothalamus does not develop properly
- Infancy: hypotonia (poor muscle tone) and difficulty feeding
- Childhood: insatiable appetite (hungry all the time), obesity
