week 1, lecture 2 Flashcards
do obese people use more or less calories than lean people in situations when not trying to lose weight?
more
satiety signals (5)
leptin, GLP1, CCK, PYY, vagal afferents
hunger signals (1)
ghrelin (released by stomach during fasting)
where do the satiety and hunger signals act on
different nuclei in the hypothalamus
arcuate nucleus of hypothalamus neurons. which increases and which decreases food intake
POMC reduce food intake and increase energy expenditure
AGRP increase food intake and reduce energy expenditure
what effect do non-esterified fatty acids have on insulin resistance?
increase it (by inactivating the insulin receptor via serine phosphorylation)
released from central fat
how do adipokines (hormones in fat cells) effect the insulin receptor?
increase sensitivity of insulin receptor and increase activity of enzymes that oxidize non-esterifired fatty acids
Anti-hyperglycemic adipokines vs Hyperglycemic adipokines
Anti-hyperglycemic adipokines: leptin, adiponectin (drops in T2DM)
- Hyperglycemic adipokines: resistin, retinol-binding-protein 4
pro inflammatory cytokines secreted by fat cells do what to insulin receptor sensitivity?
decrease it
visceral adiopcytes
recruit macrophages and activated them –> inflammatory cytokines (TNF alpha, IL6) –> increase CRP in liver
insulin resistance –> increase free fatty acids –> activate DAMPs and increase pro inflammatory cytokines
effects of obesity + inflammation
lipids cause ROS and free fatty acids circulating bing PAMP-R in adipocytes producing IL6 and TNFalpha
what is a cause of singaling inhibition of insulin resistance
serine phosphorylation of receptor
overweight vs obesity BMI
overweight >25
obese >30
waist: hip ratio for obestiy
men: >0.9
women >0.85
energy expenditure
total amount of energy we expend, measured in kcal/day
what is energy expenditure composed of
resting metabolic rate + diet-induced thermogenesis + activity-related energy expenditure (exercise activity thermogenesis + non exercise activity thermogenesis)
RMR resting metabolic rate
metabolism of an individual
at rest
* Energy requirements of respiration, circulation, etc.
energy expenditure in an individual that is at rest and has not recently eaten
AEE activity-related energy expenditure
- Exercise activity thermogenesis (EAT) – energy used during “dedicated exercise”
- Non-exercise activity thermogenesis (NEAT) – energy used when an individual is moving, but “not exercising” ! much larger component of AEE (i.e. fidgeting)
diet induced thermogenesis DIT
increase in metabolic rate associated with ingestion of food and post-absorptive heat production
how much of energy expenditure does resting metabolic rate make up>
60-75%
what is the main determinant of resting metabolic rate
fat-free mass
(main component is skeletal muscle) (also includes bone, visceral organs, ECF)
how much does resting metabolic rate vary in the same individual
varies from 2 – 10% in the same individual
▪ time of day, temperature season, etc. as well as errors in
measurement
resting metabolic rate varies how much between individuals
8-18%
what makes up the majority of total energy expenditure
resting metabolic rate >non exercise activity thermogenesis > diet induced thermogenesis >exercise activity thermogenesis
basal metabolic rate (BMR)
▪ Completely rested subjects in the morning, after 8 hours of sleep, fasting for 12 hours, and at a room temperature of between 22 – 26 Celsius
▪ 80% of variations in BMR are due to FFM variations (same as RMR)
NEAT
“portion of daily energy expenditure resulting from spontaneous physical activity that is not specifically the result of voluntary exercise”
▪ variation can be up to 2000 kcal/day in two similar- sized individuals
▪ differences in occupations, leisure activities, molecular/genetic factors, seasonal effects
▪ The most variable aspect of energy expenditure on a population basis
- 6-10% of EE in individuals with a sedentary lifestyle
- up to 50% in highly active individuals (often those that are standing or constantly moving around in their occupation)
impact of overfeeding on NEAT
minority of people, NEAT increases
majority of people, NEAT does not increase, but today EE does still increase
impact of underfeeding on NEAT and RMR
RMR and NEAT decreases
i.e. if loosing weight, EE decreases (mostly due to losses in FFM)
Studies suggest that those that undergo exercise regimens with underfeeding will not suffer as large a decrease in NEAT
models of energy expenditure
- Independent model of energy expenditure:
▪ changes in EE are independent of the energy you “budget”
for a behaviour (NEAT, EAT)
▪ Therefore, if you increase your NEAT & EAT, your total EE goes up… and it’s “easier” to lose weight - Compensation/allocation model of energy expenditure
▪ if you increase the energy expenditure in one area (EAT for example), you decrease the expenditure in another (RMR or NEAT)
compensator vs non-compensator
▪ Compensator – if a compensator is overfed, then spontaneous physical activity (NEAT) increases
▪ Non-compensator – with overfeeding, less increase in EE, mostly due to less of an increase in NEAT
effect of weight loss from caloric restriction on skeletal muscle
skeletal muscle becomes more efficient
decrease SNS activity
switch to isoforms of myosin heavy chain to expend less ATP
RMR decreases from thyroid hormone decrease and SNS decrease
what GLUT transport does exercise impact
GLUT4 –> improve glucose transport from blood to muscle and decrease insulin resistance
homeostatic pathway
stimulate eating when energy stores are low
peripheral players that sense nutrients in homeostatic pathway to modulate appetite and EE
adipose tissue, stomach, intestine, liver, pancreas, endocrine signals
central players that sense nutrients in homeostatic pathway to modulate appetite and EE
nerves and CNS nuclei
Vagus nerve, brainstem, hypothalamic nuclei, cortex, aspects of the limbic system
2 nuclei of the hypothalamus that regulate feeding in the homeostatic model
arcuate nucleus (ACN) and paraventricular nucleus (PVN)
presence vs absence of food in homeostatic model
presence of food: POMC –> ACN –> MSH –> PVN –> reduce eating and increase EE
also AGRP neurons are inhibited
satiety is mediated by increased MSH signaling, either directly (MSH release) or indirectly (inhibition of AGRP release)
serotonin signalling in the homeostatic pathway. where are they found in the brain? what does increased signalling do?
in midbrain (raphe nucleus) and project to the arcuate nucleus (ACN) in hypothalamus
increased serotonin signalling activates MSH and inhibit AGRP therefore reducing food intake and increasing energy expenditure
hedonic model of eating; which brain areas?
food intake driven by reward pathways in the brain (esp in absence of hunger)
Lateral hypothalamus, ventral tegmental area, nucleus accumbens (part of ventral striatum), limbic system nuclei
* Major neurotransmitters implicated are dopamine as well as the endogenous opioids (enkephalins, endorphins, etc.)
CNS portion of the hedonic model
lateral hypothalamus projects to VTA in midbrain where dopaminergic neurons are and which diffusely project to the nucleus accumbens, amygdala and prefrontal and orbitofrontal cortex
reward deficiency hypothesis
lean people have better activation of reward pathway
obsess are reward deprived; stratal dopamine release is impaired and decreased receptor activation
also obese have greater corticolimbic activation in presence of yummy looking food
Increased reward expectation + decreased reward upon eating! increased eating behaviour
what hormone in the pancreas effects eating
insulin
which hormones in the GI effect eating
- Stomach – ghrelin (orexigenic)
- Rest of the GI tract: GLP-1, CCK, peptide YY, oxyntomodulin
which hormones are in adipose tissue that effect eating?
Leptin, adiponectin, resistin, retinol- binding protein 4 (RBP-4), FGF-21
white fat
predominant form of adipose tissue
stores triglycerides and visceral adipose tissue
endocrine organ
brown fat
decreases with age
role in thermogenesis
mitochondria burn fat (beta oxidation) via ATP
regulated by catecholamines (dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline))
white fat into brown fat via?
exercise, cold, sympathetic stimulation
white vs brown fat
white for energy storage
brown for energy expenditure
leptin; where its found and what its secreted and inhibited by
secreted by white adipocytes when insulin present,
inhibited by catecholamines
increases post prandially
how is leptin anorexigenic?
suppresses NPY and AGRP, increases MSH secretion from arcuate nucleus of hypothalamus
obese people and leptin
Obese subjects tend to have elevated leptin levels and the hypothalamus is resistant to leptin
where is insulin secreted and in response to what?
by pancreatic beta cells in response to elevated blood glucose
where are insulin receptors in the brain and what hormone is increased
ventral stiatium
linked to increased dopamine signalling (increase hedonic pathway)
what is the only orexigenic hormone
ghrelin
what cells in the brain release ghrelin
And where is gastric found in the stomach
gastric fundus (in response to fasting)
stimulates hunger pathways (amplify AGRP and NPY, inhibit MSH) via stimulating vagus nerve
obesity and ghrelin
- Fasting levels of ghrelin are negatively correlated with BMI
- Obese patients might not suppress ghrelin as effectively after a meal
CCK, GLP1 and PYY effects in GI tract
CCK in duodenum (SI) - slows gastric emptying and increases satiety
GLP1 and PYY are more distal in the intestine but also slow gastric emptying and increases satiety
GLP1 also for insulin secretion
adiponectin
mostly in white adipose tissue
as visceral fat and insulin resistance increase, adiponectin decreases
increases insulin sensitivity
decrease fat accumulation
resisting and retinol binding protein 4 (RBP4) have what effect on insulin resistance
increase it
adiponectin has what effect on insulin sensntivity
increases insulin sensitivity (opposite to resisting and RBP4)
SLIDE 45 and 46 chart
xx
HPA axis and gut microbiota via which hormone
chronic cortisol elevations
vagus nerve impact on gut microbiome
intestinal distention via mechanoreceptors and vagal chemoreceptors via entereoendocrine cells
obesity and gut microbiome
increased gut permeability allows LPS to enter circulation = inflamed and insulin insensitive
enteroendocrine cells (serotonin, ghrelin, CCK, GLP1, PYY) alter secretions in response to SCFAs
vagus nerve
what does gut microbiome produce
dopamine, serotonin, GABA,
SCFAs regulate satiety (increase PYY and GLP1, stimulate vagus nerve, induce anorexigenic signals, increase leptin, induce thermogenesis)
bifidobacterium and lactobacillus relate to leptin and ghrelin how
positive to leptin (satiety) and negative to grhrelin (hunger)
h pylori eradication increases
certain bacteria that correlate with decreased gremlin (hunger)
CCK impacts food intake how via vagus nerve
reduces it
where is GLP 1 released
intestinal epithelia enteroendriceine cells in small intestine and large intestine
function of GLP1
increase insulin, reduce glucagon, delay gastric emptying, regulate appetite
do obese humans have more or less SCFA produced
Increased energy harvest! increased fermentation! increased production of short chain fatty acids (SCFA’s)
Obese humans have elevated SCFA production
