4. The science of obesity Flashcards
what are some key drivers that promote overconsumption of food?
The increased availability of processed, affordable and effectively marketed food, abundance of sugar-sweetened beverages,
economic growth, behavioural changes and rapid urbanization in lowand middle-income countries
what is the most important player in obesity?
brain
how does the hypothalamus act in obesity?
homeostatic area - role in energy homeostasis by regulating energy intake and expenditure
complex control of appetite
what is the hunger centre that controls feeding behaviours?
the arcuate nucleus of the hypothalamus
what are 2 sets of neuronal population that reside in the arcuate nucleus?
neurons co-expressing agouti-related protein (AgRP) and neuropeptide Y (NPY)
what activates AgRP/NPY
neurons in the arcuate nucleus?
hormonal and neural signals from the gut, adipose tissue, and the peripheral organs
if AgRP/NPY neurons in the arcuate nucleus get activated, what happens?
stimulate hunger sensation and trigger food-seeking behaviours
the activity of these AgRP/NPY neurons is rapidly reduced upon access to food - these neurons are primarily involved in food-seeking or the homeostatic control of appetite, but are less likely to normally drive xxx?
food consumption
how do these AgRP/NPY neurons mediate their downstream effects?
via the melanocortin-4 receptors located in the nearby paraventricular nucleus
The AgRP/NPY neurons project directly to the second set of neurons that co-expressing what?
pro-opiomelanocortin (POMC) and
cocaine- and amphetamine-regulated transcript (CART)
what do pro-opiomelanocortin (POMC) and
cocaine- and amphetamine-regulated transcript (CART)?
suppress food intake by firing through the downstream inhibitory Y1 and gamma-aminobutyric acid (GABA) receptors
The homeostatic control of appetite in the arcuate nucleus is influenced by a
number of factors including?
the nutritional status of the organism, nutrient
sensing and availability, taste, smell and food preferences.
what is hedonic eating?
neural systems that involve emotional, pleasurable and rewarding aspects of eating
Hedonic eating is based on the feelings of reward
and pleasure that are associated with …?
seeing, smelling or eating food
in hedonic eating, the signals are transmitted by which pathways?
dopaminergic, opioid and endocannabinoid pathways
what does dopamine signal in response to emotional triggers, such as sadness, or environmental triggers, such as the smell or sight of delicious food?
desire to eat
when are Opioid and endocannabinoid
signals released ?
when food is consumed, and are responsible for
the feeling of pleasure associated with eating
Some people living
with obesity may have a heightened anticipation (wanting) of the
pleasure of food driven by a dysregulation of which?
dopamine
what is dysfunctional and is downgraded compared to the anticipation, resulting in a need to overeat to achieve the level of the anticipation?
the pleasure of eating the food (liking)
what is the target for the treatment of obesity?
controlling dysregulation between wanting and liking of eating
where is a brain region that is tied to consummatory behaviours and mediates positive reinforcement?
lateral hypothalamus
Hedonic eating is also
controlled by which system?
corticolimbic system, which consists of cortical areas, basal ganglia, hippocampus and amygdala in the midbrain.
which is responsible for executive functioning and overriding primal behaviours driven by the mesolimbic system
cognitive lobe
Cognitive functioning works well under optimal conditions including.. which help to deal with adverse situations
rest, oxygen, decreased stress and supports
excessive eating often occurs in the evening - why?
suboptimal conditions, following the accumulation of
stressors throughout the day, fatigue and lower levels of will power
There are also other areas of executive dysfunction in some people
living with obesity, primarily in ..?
decision making,
response inhibition
and cognitive flexibility
Current research indicates that there is significant crosstalk between
homeostatic and hedonic eating, which is mediated by many of what signals?
endocrine and gut-derived signals
which act on the dopaminergic neurons in the midbrain to modulate food reward and hedonic eating?
Leptin, insulin, ghrelin, glucagon-like peptide-1 (GLP-1)
what is another appetite-suppressing network?
calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN)
what does calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) suppress?
eating
when are PBN-CGRP neurons activated and what signal do they provide?
when food intake;
signal of satiety
what is actively involved in the alignment of fasting and feeding
with the sleep/awake cycle?
the hypothalamic circadian clock network
how does the hypothalamic circadian clock network work?
the AgRP neurons coordinate the leptin response and glucose metabolism with arousal
what does Cognitive areas in the prefrontal cortex execute?
control on the decision to eat and the food choices
what are two key hormones that communicate to the homeostatic control of the long-term energy reserve and nutritional status in the body?
Leptin and insulin
what is a fat-derived hormone that is secreted by white adipose tissue in proportion to the body’s fat mass?
Leptin
Leptin and insulin bind to their respective receptors in the arcuate nucleus to do what?
decrease food intake and increase energy expenditure
In states of decreasing body fat stores, circulating leptin levels fall and
signals what?
the hypothalamus to inactivate the POMC/CART-expressing
neurons to promote feeding;
while simultaneously lowering its inhibitory effect on the AgRP/NPY-expressing neurons to increase appetite
and decrease energy expenditure
As adiposity increases, leptin levels
increase in the circulation and exert negative feedback to …
suppress
appetite to prevent further weight gain
leptin resistance
also occurs in which people?
who have excessive adiposity
what are potent anorexigenic gut hormones that are secreted by enteroendocrine L-cells in the small bowel in response to food ingestion?
GLP1 - powerful incretin;
peptide YY3-36 (PYY) - delays gastric emptying
how are GLP1 and PYY working against obesity?
promote satiation (meal termination) and satiety by activating the POMC/PYY neurons while reducing hunger via the AgRP/NPY neurons
what is another peptide secreted concurrently with GLP-1 and PYY?
Oxyntomodulin - enhances satiety and decreases food consumption
when is CCK secreted and what does it do?
in response to fat and protein ingestion;
stimulates gall bladder contractility and pancreatic enzyme secretion, and slows gastric emptying;
mediates fat and protein satiation as well as glucose-regulatory effects on the hypothalamus, and also via the vagal afferent fibres
what is pancreatic polypeptide (PP)?
secreted by F-cells in the pancreatic islets;
released during the postprandial phase to enhance satiety
what is an orexigenic hormone produced in the gastric fundus which increases hunger and stimulates food intake?
ghrelin
Upon food ingestion, sensory information on the volume and
composition of the meals, and notably satiation, is relayed to where?
nucleus tract solitarius (NTS) in the brainstem by the vagal afferent fibres
what does NTS in the brainstem do when they have information?
integrates and transmits the signals to the homeostatic control pathways in the hypothalamus, primarily influencing satiety and meal termination
how many genetic regions are now known to influence obesity traits?
more than 140
what are examples of mutations in genes involved in appetite control?
5 Loss of function mutations in leptin, leptin receptor,
pro-opiomelanocortin and melanocortin receptor-4
6 Eleven monogenic forms of obesity have been discovered. They are rare, and the most common cause is what?
heterozygous mutation in MC4R - 2-5% of severe obesity in kids
what are endocrine causes of obesity ?
Cushing disease;
hypothyroidism;
pseudohypoparathyroidism;
- 1% of all cases of obesity
what do syndromic forms of obesity include?
Prader-Willi, Bardet-Biedl and Cohen syndromes
Leptin binds to specific receptors, which belong to …?
the interleukin-6 receptor family of class I cytokine receptors
Leptin’s effect is
not limited to appetite regulation and energy homeostasis; it also
exerts a wide array of…?
endocrine and metabolic influences
which suppresses insulin secretion from pancreatic β cells and plays a role in insulin resistance?
Leptin
which hormone is abundantly produced by adipocytes, and exerts pleiotropic effects on a broad array of physiological processes, including energy homeostasis, vascular function, systemic
inflammation and cell growth?
Adiponectin
what is adiponectin’s most important function in obesity?
an insulin-sensitizing agent which stimulates insulin gene expression and secretion
Adiponectin levels are inversely correlated in xxxx
and xxxx, and reflect xxxx
Adiponectin levels are inversely
correlated in obesity and insulin-resistant states, and reflect wholebody insulin sensitivity
Circulating adiponectin levels are lower in
people with …
obesity, polycystic ovarian syndrome, individuals with
impaired glucose tolerance or type 2 diabetes.
Decreased adiponectin
level, or hypoadiponectinemia, is associated with increased risk for …
developing type 2 diabetes in otherwise healthy people
in which condition can adipose tissue dysfunction may develop?
continuous positive energy balance in people with an impaired expandability of subcutaneous adipose tissue
The inability to store excess
calories in healthy subcutaneous fat depots can lead to increased
visceral fat accretion and ectopic fat deposition in which organs?
liver, muscle, epicardium of the heart
Adipose tissue expansion often leads
to dysfunctional changes, which are characterized by …?
inflammation,
inappropriate extracellular matrix remodelling and insufficient angiogenic potential.
what is thought to be the driver for
adipose tissue dysfunction?
cellular hypoxia
A consequence of dysfunctional adipose tissue, especially in the visceral depots, is augmented production of what?
fat-derived proinflammatory cytokines, or adipokines
what are adipokines?
tumour necrosis factor-α, interleukins,
C-reactive protein and monocyte chemotactic protein-1
what can adipokines accelerate the progression to?
fibrosis,
accelerated angiogenesis,
apoptosis and autophagy by promoting the migration of immune cells into adipose tissue
dysfunctional adipose tissue
can lead to the development and progression of ..?
a myriad of adiposity-related comorbidities, such as type 2 diabetes, hypertension,
dyslipidemia, nonalcoholic fatty liver disease, cardiometabolic risks
and atherosclerotic cardiovascular disease.
what is brown adipose tissue involved in?
whole-body energy homeostasis through non-shivering thermogenesis
Recruitment of beige adipocytes, or
“beiging” of white fat, can be induced by ..
chronic exposure to cold
temperatures and, to some extent, exercise
what are Beige adipocytes?
inducible forms of thermogenic adipocytes
Recent data suggest that gut microbiota
may influence weight gain and insulin resistance through different
pathways, including ?
energy harvesting from bacterial fermentation,
short-chain fatty acid signalling and bile acid metabolism
Human studies have indicated that the
primary bacteria involved in weight homeostasis are?
firmicutes - promote weight gain;
bacterioidetes - more in lean individuals
The predominant theory between
the link of obesity and cardiometabolic risk is described as obesity
inducing an insulin resistant state through two primary mechanisms - which are?
defective insulin signal, and chronic tissue inflammation
and increased adipose tissue macrophages
Adipose tissue is a
source of increased levels of which?
circulating free fatty acids due to increased lipolysis
In the liver, increased free fatty acid flux results in ?
increased glucose production, triglyceride synthesis and secretion
of very low-density lipoprotein
