Obesity Flashcards
(138 cards)
1
Q
What is the NHS definition of obesity?
A
As having excessive adipose tissue which is detrimental to health.
2
Q
Does everyone cope with excessive adipose tissue the same way?
A
No the ability of an individual to cope with excessive adipose tissue varies between individuals.
3
Q
What is a frequent metric used to define overweight or obese?
A
BMI (Body Mass Index) is a frequent metric.
4
Q
What does BMI not take into consideration?
A
It does not take into consideration body composition.
5
Q
What is obesity understood as a clear driver of?
A
Multimorbidity.
6
Q
Is simply being obese a risk factor for other pathologies?
A
Yes simply being obese is a significant risk factor for various other pathologies.
7
Q
What are some metabolic multimorbidities linked to obesity?
A
They include type II diabetes and fatty liver disease.
8
Q
What are some reproductive effects linked to obesity?
A
They include PCOS and male infertility.
9
Q
What are some pulmonary multimorbidities linked to obesity?
A
They include COPD and sleep apnoea.
10
Q
What are some mental health implications linked to obesity?
A
They include ADHD; depression; anxiety; and dementia.
11
Q
How does obesity impact mortality and life expectancy?
A
It leads to increased mortality and decreased life expectancy.
12
Q
Is the number of children diagnosed with obesity increasing?
A
Yes an increasing number of children are being diagnosed with obesity.
13
Q
Globally what percentage of people are overweight?
A
46% of people are overweight.
14
Q
Globally what percentage of people are obese?
A
16% of people are obese.
15
Q
In theory how should weight loss strategies work?
A
Weight gain results from a positive energy balance (caloric intake > energy expenditure) and losing weight occurs through generating a negative energy balance (caloric intake < caloric expenditure).
16
Q
What contributes to the ‘obesogenic’ nature of the current environment?
A
Factors include the rise of sedentary lifestyles and ultra-processed food.
17
Q
What does the obesogenic environment make difficult?
A
It has become increasingly difficult to maintain neutral energy balance.
18
Q
Are simple lifestyle modification and behavioural changes clinically effective for significant weight loss?
A
No, they are not seen to be clinically effective for people to achieve significant weight loss.
19
Q
What is needed for weight loss therapies?
A
Scalable, safe, and effective weight loss therapies are needed.
20
Q
What reduction in body weight can standard behavioural treatment produce?
A
Approximately a 3% body weight reduction.
21
Q
What happens to weight lost with standard behavioural treatment?
A
Individuals are seen to regain the weight quickly.
22
Q
What reduction in body weight can behavioural modification with meal replacement strategies initially produce?
A
Approximately a more significant 15% loss of body weight.
23
Q
What happens to weight lost with behavioural modification and meal replacement?
A
They are also seen to regain the weight quickly.
24
Q
What weight loss strategy produces the largest and most sustained weight loss?
A
Bariatric surgery is seen to produce the largest and most sustained loss of weight.
25
What is the typical weight loss from bariatric surgery?
Up to **~30%** of body weight.
26
Does weight loss from bariatric surgery persist?
Yes, unlike behavioural and diet interventions, weight loss studies demonstrate that this weight loss appears to **persist in the years to follow treatment**.
27
How does some bariatric surgery work structurally?
Surgery is performed such that nutrients **bypass the duodenum** and nutrient delivery is directly to the jejunum.
28
Is bariatric surgery a permanent change?
Yes, bariatric surgery (like RYGB) is a permanent, unmodifiable change to the GI system.
29
What are the limitations of bariatric surgery?
It is irreversible, and **NOT a scalable, cost-effective strategy** to roll out worldwide.
30
What do the limitations of scaling bariatric surgery prompt the need for?
The development of **pharmacotherapies** to manage obesity moving forwards.
31
What is the aim of pharmacotherapies compared to bariatric surgery?
The aim would be to **mimic the efficacy of bariatric surgery** using pharmacological agents.
32
What are the characteristics of a good anti-obesity drug?
It should: **sizeably reduce weight**; **sustainably maintain weight loss**; **reduce risk of multimorbidity**; be devoid of dangerous side effects.
33
What dangerous side effects should a good anti-obesity drug be devoid of?
Adverse cardiovascular effects, increased suicidal risk, drug dependence/abuse.
34
What was one of the first weight loss therapeutics developed in the 1900s?
**DNP** was one of the first.
35
How does DNP disrupt metabolism?
DNP disrupts the electron transport chain and uncouples nutrient intake to energy production/storage.
36
What does DNP create that affects ATP production?
DNP creates a **proton leak** that prevents the electrochemical coupling of nutrient/glucose intake to the production of ATP by ATP synthase.
37
What were some devastating side effects of DNP in initial clinical trials?
Hyperpyrexia (overheating); rash, breathlessness; sweating; cataracts.
38
Did DNP have severe health side effects?
Yes, severe health side effects contributed to significant death rates in those taking DNP and its derivatives.
39
Is DNP still seen today?
Yes, DNP is still being seen in **bodybuilding supplements** in the present day.
40
What were 'Rainbow pills' from the 1960s?
An **amalgamation of various drugs**.
41
What types of drugs were included in 'Rainbow pills'?
Diuretics, amphetamines, thyroid hormones, laxatives, phenolphthalein, and herbal ingredients.
42
How does D-amphetamine affect energy balance?
It **decreases appetite** and **increases locomotion** working on both input and output sides of the energy balance equation.
43
What is the pharmacological mechanism of amphetamines on signalling?
Amphetamines modulate **DA and NA signalling** by altering vesicular release and reuptake mechanisms.
44
What does amphetamine modulation affect?
Metabolic rate and motivation to feed.
45
How do thyroid hormones act to increase energy output?
They act to increase **BMR** and promote **thermogenesis**.
46
How do thyroid hormones act on lean muscle mass?
By affecting intracellular calcium levels and signalling.
47
How do thyroid hormones act on brown adipose tissue?
Through **uncoupling protein 1**.
48
What were 'Rainbow pills' a great example of according to the source?
**Personalized medicine**.
49
What were severe side effects of 'Rainbow pills'?
**Severe cardiovascular events** leading to death.
50
What did the side effects of 'Rainbow pills' promote?
The need for the FDA to most strictly scrutinise dietary supplements before they enter the marketplace.
51
How can an agent bypass FDA approval and rigorous clinical trials?
If it is marketed as a **dietary supplement**, it can bypass FDA approval.
52
Why did many anti-obesity drugs developed in past decades not take off?
Due to **severe side effects** like tachycardia, depression, and suicidal ideation.
53
What are GIP and GLP-1?
They are **incretins**; gut peptides released from enteroendocrine cells.
54
Where are incretins released from?
Enteroendocrine cells lining the proximal small intestine following meal ingestion.
55
What is the role of GIP and GLP-1 in insulin release?
They are critical components of the incretin axis driving the **augmentation of postprandial insulin release** through direct and indirect engagement of pancreatic β cells.
56
What was the initial intent for developing GIP and GLP-1 agents?
With the intent to act as a **diabetes treatment**.
57
What was noted in early trials of GLP-1 therapy for type II diabetes?
Both a **control of blood glucose** concentration and reports of increased satiety and reduction of body weight.
58
What did this early finding suggest about GLP-1 signalling?
It was the first indication that GLP-1 signalling affects central satiety signalling and body weight.
59
What did preclinical studies demonstrate about GLP-1 delivery into the brain's ventricular system?
It induces **acute anorexia** in rats in a dose dependent manner.
60
What brain centres do animal studies demonstrate GLP-1 activate?
Key **feeding centres** in the brain specifically within the nuclei of the hypothalamus.
61
How was increased neuronal activation measured in the hypothalamus following GLP-1 administration?
By increased **cFos signal**, particularly in the PVN.
62
What do lesion studies demonstrate is key to regulating appropriate appetitive behaviour?
A functional **hypothalamus**.
63
Where are GLP-1 receptors widely expressed in the brain?
Within the **hypothalamus** (e.g; in PVN) and in the **brain stem** (dorsal vagal complex region including the area postrema and NTS).
64
Why do brainstem regions like the area postrema and NTS have privileged access to peripheral hormones?
Due to **leaky BBB** (Blood Brain Barrier) at these sites.
65
Are GLP-1R agonists administered peripherally able to access feeding centres in the brain?
Yes, GLP-1Rs expressed in feeding centres (within hypothalamic and brainstem targets) are accessed by peripheral GLP-1R agonists.
66
How is access of peripheral fluorescent GLP-1 agonists demonstrated?
Fluorescent labelling is seen in both brain stem and hypothalamus.
67
What are the canonical yin-yang neurons that regulate appetite within the brain?
**POMC** and **AgRP** neurons.
68
What happens when AgRP neurons are activated?
AgRP neuron activation drives **hunger** leading to the release of AgRp and NPY which **decrease satiety**.
69
What happens when POMC neurons are activated?
POMC neuron activation drives **satiety**, leading to the release of α-MSH, which **reduces drive to eat**.
70
Are GLP-1Rs expressed on POMC neurons?
Yes, GLP-1Rs are expressed on POMC neurons.
71
What do electrophysiological recordings show about POMC neurons and GLP-1 administration?
They demonstrate the **depolarisation of POMC neurons** upon GLP-1 administration.
72
What does this evidence demonstrate about how GLP-1 engages satiety neurons?
It demonstrates how GLP-1 engages satiety neurons within feeding centres of the brain to reduce appetite.
73
Is GLP-1 activity only localised to feeding centres in the hypothalamus?
No, GLP-1 activity is not localised only to feeding centres; it has activity across the brain and in the peripheral nervous system.
74
Where does GLP-1 specifically act in the peripheral nervous system?
Specifically acting at the **vagus nerve**.
75
How does GLP-1 likely act to decrease the drive to eat?
GLP-1 likely acts across a **variety of organ systems and appetite circuits**.
76
What did pre-clinical data supporting weight loss with GLP-1 agonists promote?
Drug companies developed longer acting; more efficient versions of GLP-1 receptor agonists.
77
What GLP-1R agonist was developed for weight loss therapy?
**Semaglutide** was developed.
78
Did semaglutide show significant clinical efficacy for weight loss?
Yes, it showed significant clinical efficacy.
79
What weight loss did semaglutide result in over 18 months?
It resulted in **18% weight loss** in 18 months.
80
How did semaglutide's therapeutic effect compare to some other drugs?
It was significantly greater than some other drugs, like cannabinoid receptor antagonists.
81
How did semaglutide's efficacy compare to diet and behavioural modifications?
It was more efficacious but still less than bariatric surgery.
82
Do individuals maintain weight loss on GLP-1 agonists after stopping the drug?
No, individuals maintain weight loss whilst actively taking the agent however, they are seen to **regain weight upon removal of the drug**.
83
What are some side effects of GLP-1 agonists?
Side effects include lack of blood glucose control, nausea, and GI side effects.
84
What are major reasons patients and physicians stop GLP-1RAs?
**Nausea; vomiting; and GI side effects**.
85
What are the aims for the next GLP-1 agents?
To: **augment metabolic benefits**; **minimise adverse events** (nausea); and **expand therapeutic index**.
86
What therapeutic strategies are currently being considered?
**Combinatory therapeutics** are now considered.
87
What has recent pharmacology highlighted about GIP signalling for obesity treatment?
The additional therapeutic benefits of leveraging the effects of GIP signalling for the treatment of obesity.
88
How does GIP act regarding insulin and sensitivity?
GIP acts to drive **insulin secretion** and enhances **insulin sensitivity**.
89
Why was GIP suggested for inclusion in GLP-1 therapeutics initially?
To improve blood glucose control, hoping it could improve the therapeutic index of GLP-1 receptor agonists.
90
Have recent studies shown GIP-R agonism affects nausea?
Yes, recent studies have shown that GIP-R agonism **attenuates nausea and aversion** in preclinical models.
91
What unexpected wins were seen for GIP-based combinatorial therapies in animal studies?
Improved glucose handling and importantly a **synergistic effect on body weight and food reduction**.
92
Do agonists for the GIP-R given in isolation elicit significant body weight reductions?
They elicit **modest reductions** in body weight in preclinical and clinical studies.
93
Has the GIP-R signalling axis proven effective as a co-target?
Yes, it has proven to be an effective co-target for the enhancement of weight loss; improvement of glycaemic control; and reduction of emesis.
94
What correlates with potent weight loss for GIPR/GLP-1R co-agonism?
Decreased food intake correlates with potent weight loss.
95
What does the correlation between weight loss and decreased food intake suggest about the mechanism of co-agonists?
It suggests underlying **central mechanisms**.
96
What dual agonist showed more effective weight loss than semaglutide?
**Tirzepatide** (TZP) a dual agonist was seen to induce more effective weight loss.
97
What idea did Tirzepatide's success cement?
The idea for the role of GIP in modulating central circuits to reduce body weight.
98
Is GIP-R expressed extensively in the CNS?
Yes, GIP-R is expressed extensively throughout the CNS.
99
Is central GIP-R expression necessary for the synergistic weight loss from GIP-R/GLP-1R co-agonism?
Yes, central GIP-R expression is necessary.
100
What does this indicate about the GIP-R signalling axis?
It indicates the importance of the GIP-R signalling axis in the brain and the need to understand its role in regulating energy balance.
101
What happened when mice with CNS-specific knockout of GIP receptors were treated with dual agonists?
Removing central GIP expression **ablated the ability of the dual agonist to decrease body weight** beyond that achieved by GLP-1 agonist alone.
102
What does the CNS-specific GIP knockout mice model demonstrate?
It demonstrates that **central GIP-R expression is necessary** for body weight loss in response to GIP/GLP-1 co-agonist.
103
Does chemogenetic activation of Gipr neurons in the hypothalamus acutely reduce food intake?
Yes, chemogenetic activation of Gipr neurons in the hypothalamus acutely reduces food intake.
104
Did hypothalamic KO of Gipr in mice ablate weight loss in response to cotreatment with long-acting GIP and GLP1R agonists?
No, hypothalamic KO of Gipr **failed to ablate weight loss**.
105
What does the hypothalamic KO study suggest about other Gipr populations?
It suggests that other Gipr neuronal populations may have an important role in regulating energy balance.
106
Where is GIP receptor expression seen in the brain similarly to GLP-1?
In the **hypothalamic** and **brainstem** regions.
107
Have post-mortem studies confirmed GIP receptor expression in the human hypothalamus/brainstem?
Yes, post-mortem brain studies in humans confirmthat GIP receptor is expressed in the hypothalamus/brainstem.
108
Is the data seen in mice likely translatable to humans regarding GIPR expression?
Yes, data seen in mice is likely translatable to humans.
109
Is peripheral administration of GIPRAs able to induce neuronal activation in key brain regions?
Yes, Peripheral administration of GIPRAs is able to induce neuronal activation.
110
What key hypothalamic nuclei show increased cFos expression from peripheral GIPRAs?
**Arcuate nucleus** and **PVN**.
111
Does the brainstem also show activation from peripheral GIPRAs?
Yes the brainstem shows activation.
112
Is there heterogeneity in terms of GIPR expression neuronal populations?
Yes there is **huge heterogeneity**.
113
What do current works aim to understand about GIPR circuits?
What the relative contribution of each of these different circuits is to appetite regulation.
114
Do Gipr neuron populations leverage different anorexigenic pathways?
Yes Gipr neuron populations leverage different anorexigenic pathways.
115
How do Gipr neuron populations engage different behavioural regulation modes?
Depending on their **neuroanatomical location** to affect feeding and energy balance.
116
Do GIPR neurons in the DVC engage separate anorexigenic pathways from GIPR in the hypothalamus?
Yes GIPR neurons in the DVC engage separate anorexigenic pathways from GIPR in the hypothalamus.
117
What models have been used to dissect the potential of GIPR expression in discrete neuronal populations?
**Chemogenetic models** have been used.
118
What regions were targeted in chemogenetic models to influence feeding behaviour?
Hypothalamus or DVC.
119
What happened when Gipr neurons were stimulated in both brainstem and hypothalamus regions in chemogenetic studies?
Stimulation of Gipr neurons in both regions **suppressed feeding**.
120
Did stimulation in the brainstem and hypothalamus suppress feeding through the same mechanism?
No they suppressed feeding but through **distinct-regional mechanisms**.
121
What was the effect of activating brainstem GIP receptors?
Activation brainstem receptors led to a **decrease in energy expenditure**.
122
What was the effect of activating hypothalamic GIP receptors?
Activation of hypothalamic receptors led to an **acute increase in energy expenditure**.
123
What do these findings indicate about hypothalamic and DVC GIPR populations?
It indicates that hypothalamic and DVC GIPR populations engage distinct anorexigenic mechanisms.
124
What do current work aim to understand about these different GIPR circuits?
How these different circuits **synergize and interconnect** with each other across these two different sites.
125
How close are combinatory therapies getting to the bariatric surgery weight loss benchmark?
Combinatory therapies inch even closer to the bariatric surgery benchmark of 30% weight loss.
126
What weight loss was TZP (a dual agonist) able to generate?
TZP was able to generate **~22% weight loss**.
127
What class of drugs has recently been investigated?
GIP/GLP-1/glucagon **tri-agonists** have been investigated.
128
What do current clinical trials show for tri-agonists?
They show very successful weight loss.
129
What is Retatrutide?
Retatrutide is an agonist of the **glucose-dependent insulinotropic polypeptide**; **glucagon-like peptide 1**; and **glucagon receptors**.
130
What were the findings in mice studies with retatrutide treatment?
It led to **weight loss**; reduced fat mass; decreased blood glucose and insulin levels in obese mice.
131
What was the mechanism attributed to the effects seen in mice studies with retatrutide?
Increased energy expenditure and lipid oxidation.
132
What were the findings in adults with obesity treated with retatrutide for 48 weeks?
Substantial reductions in body weight were observed in a phase 2 trial.
133
Is the weight loss reported through retatrutide the greatest reported pharmacologically to date?
Yes to date this is the greatest weight loss reported through a pharmacological agent.
134
How do the results observed with retatrutide compare to bariatric surgery?
Similar results observed in those who underwent bariatric surgery.
135
What is the mechanism of action attributed to tri-agonists like Retatrutide?
The GIP/GLP-1 receptor co-agonism is enhanced by **glucagon receptor activation** and augmentation of energy intake; substrate utilisation; and energy expenditure.
136
How do GIP/GLP-1 dual agonists modulate the energy balance equation?
They modulate the **energy input side**.
137
How do triple agonists modulate the energy balance equation?
Triple agonists modulate **both input and output sides**.
138
What is one of glucagon's key roles regarding energy?
To **increase energy expenditure**.
