Lecture 5: Obesity

Question 1

Obesity: Side Notes

Answer 1

• Obesity is an exaggeration of normal adiposity and is a central player in the pathophysiology of diabetes mellitus, insulin resistance, dyslipidemia, hypertension, and atherosclerosis, largely due to its secretion of excessive adipokines.
• Obesity is a major contributor to the metabolic dysfunction involving lipid and glucose, but on a broader scale, it influences organ dysfunction involving cardiac, liver, intestinal, pulmonary, endocrine, and reproductive functions.
• Inflammatory, insulin-resistant, hypertensive, and thrombotic-promoting adipokines, which are atherogenic, are counterbalanced by anti-inflammatory and anti-atherogenic adipocyte hormones such as adiponectin, visfatin, and acylation-stimulating protein, whereas certain actions of leptin and resistin are pro-atherogenic.
• Adiponectin is protective against liver fibrosis due to its antiinflammatory effect, whereas inflammatory cytokines such as tumor necrosis factor-α are detrimental for both fatty liver and pancreatic insulin release.
• Obesity contributes to immune dysfunction from the effects of its inflammatory adipokine secretion and is a major risk factor for many cancers, including hepatocellular, esophageal, and colon

Question 2

Functions of The Endocrine System

Answer 2

• Differentiation of reproductive system and CNS in fetus
• Stimulation of growth and development
• Coordination of the male and female reproductive systems
• Maintenance of internal environment
• Adaptation to emergency demands of body – fight or flight – high levels of glucose à homeostasis

Question 3

Defining the Obesity Epidemics

Answer 3

Difficult to define obesity in a clinical standpoint

Can look at different imaging modalities to look at fat and the location of the adiposity – extracellularly (peripheries) or in intracellularly (in the organs – intramyocellular lipids or fat in the heart)

Imaging (BMI)​

• different ways to look at defining obesity
• typically use BMI – a calculation that is body mas per kg relative to their high in meter 2rd
• BMI ranges from low to high in terms of measuring obesity
  
  • Underweight (12-18.5)
  • Normal (18.5-25)
  • Excessive (30-35)

Question 4

Limitations of BMI

Answer 4

• BMI does not look at the fat distribution w/n an individual
• Individuals who have a higher muscle mass may on the BMI scale seem to be overweight or excessively obsess based on the BMI calculation
• BMI may help to define obesity but not help us to look at body composition

Question 5

Mechanisms + Consequences for CVS & Diabetes

Answer 5

Atopic fat - can be in and around the heart

Question 6

Risk Factors For Obsesity

Answer 6

• Genetics – fairly small 5-10% of cases
• Environmental – family history, types of foods your exposed to, the community you live in, the environment you grow up in, how accessible they are to greenspace and parks so that one could participate in activities, safety
• Physiological – can preexposure us to obesity
• Psychological – poor self esteem, disordered eating à lead to obesity
• Sociological – screen time, habitual physical activity levels, food choices

Question 7

Obesity & Clustering of Risk Factors

Answer 7

• Dyslipidemia – high cholesterol
• Hypertension
• Insulin resistance / Impaired glucose tolerance
• Type II diabetes mellitis
• Non-alcoholic steatohepatitis
• Abdominal obesity / Fatty Liver Disease
• Abnormal cholesterol
• Increased BP
• Depression
• Asthma / OSA (obstructive sleep apnea)

Question 8

Inflammatory Adipokines in Obesity

Answer 8

• Highlights the role of lipotoxicity and inflammation on obesity
• White adipose tissue à releases a series of adipokines (lipotoxic + inflammatory)
• Adipokines produce inflammation which produces insulin resistance in type 2 diabetes -Associated with infiltration of macrophages and immune dysfunction
• Increase in adipose tissue is associated with particular hormones (i.e. activation + increases we seen in the ROSS system – renin, angiotensinogen, angiotensin tend to be activated and have consequences down the line
• All of the factors combined have a role on obesity and the progression of obesity in other clinical manifestations including diabetes + heart disease + metabolic syndrome

Question 9

Answer 9

• Adipose tissues the release of adipokines and macrophages that act to decrease insulin sensitivity
• macrophages also contribute to a enhanced inflammatory sate + as immune stimulators they enhance certain protein kinase and transcription factors –> can play a role in inhibiting the glute for the transporter of glucose = contributing to insulin resistance
• The processive proinflammatory states resulting from obesity + accumulation of adipose tissue promotes the insulin resistance and perpetuates atherogenisis throughout its development – tend to see the dev of plc formation + thrombosis
• The adipokine releases triggers the proliferation of t-cells, NF kappa B à perpetuates inflammation and hyperglycemia
• There are so many implications in the accumulation of adipose tissue and the development of both insulin resistance and atherosclerotic

Question 10

Therapeautic Options: lifestyle modifications

Answer 10

• Prescribing and supporting intensive lifestyle modification as the prerequisite for any treatment
  
  • Dietary
  • Physical activity
  • Behavioral

Question 11

Therapeutic Options: Metformin

Answer 11

• ˜AMP kinase activator
• ˜AMP kinase is the metabolic master switch that controls flux through metabolic pathways
  
  • adipocyte lipolysis – breakdown of fat
  • skeletal muscle fatty acid oxidation
  • stimulation of glucose uptake induced by muscle contraction
• ˜AMPK is also activated by muscle contraction!
• • Given to individuals with type 2 diabetes*
• • Is similar to exercise*
• • Exercise is known to be an ANP kinase activator – promotes the formation of glucose uptake and prevent further weight accumulation*

Question 12

Therapeutic Options: Surgery

Answer 12

• Bariatric surgery
  
  • BMI above 50 kg/m2
  • BMI above 40 kg/m2 with severe comorbidities

Indicated for adults in cases where lifestyle modifications and therapies have failed

Question 13

Obesity and Implications for CV Disease and Diabetes

Answer 13

• Reactive oxygen species + may have an impact on accumulated fat and metabolic syndrome

Question 14

Hypothyroidism

Answer 14

• Primary hypothyroidism
  
  • More common
  • Due to a disease in the thyroid
  • thyroid stimulating levels are high
• Congenital hypothyroidism
  
  • Not as common
  • Disease of the hypothalamic and pituitary glands
  • †Thyroid stimulating levels are low

Is associated with moderate weight gain, is not a major factor in the obesity epidemic

Question 15

Adrenal Cortex

Answer 15

• Stimulated by adrenocorticotropic hormone (ACTH)
• Glucocorticoid hormones
  
  • Direct effects on carbohydrate metabolism
  • Anti-inflammatory and growth-suppressing effects
  • Most potent naturally occurring glucocorticoid is cortisol (associated with stresss)

outer region; is stimulated by the adrenocorticotropic hormone (acts as a precursor for the development of glucocorticoid hormone release

80% of an adrenal gland’s total weight

Zona glomerulosa

Zona fasciculata

Zona reticularis

Question 16

Adrenal Medulla

Answer 16

• Chromaffin cells (pheochromocytes)
  
  • Secrete the catecholamines epinephrine (majority) and norepinephrine
• Release of catecholamines has been characterized as a “fight or flight” response
• Chronic levels of Catecholamines have implications for blood glucose regulation àassociated with hyperglycemia

Linked to type 2 diabetes + obesity

Question 17

Disorders of The Adrenal Cortex

Answer 17

• Cushing’s disease
  
  • Excessive anterior pituitary secretion of ACTH from the interior pituitary glands
• Cushing’s syndrome
  
  • Manifestations resulting from chronic excess cortisol

Complications: obesity, diabetes, immune suppression and mental health status changes

Question 18

Craniopharyngioma

Answer 18

• Rare type of noncancerous brain tumor
• Begins near the brains pituitary glands
• As the tumor grows it can effect the function of the pituitary glands and other structures
• Can occur in children
• Can be occurred
• Obesity occurs following surgical resection

Question 19

Craniopharyngioma - Pathophysiology

Answer 19

• Damage to hypothalamic nuclei and neuronal circuits involved in appetite and body weight regulation
• A primary defect of insulin hypersecretion due to hypothalamic damage-induced vagal efferent stimulation with increased weight gain and compensatory insulin resistance
• Leptin, a hormone secreted by adipose tissue which signals satiety (feelinh of fullness after a mearl) at the hypothalamus, is elevated in children with craniopharyngioma, likely reflecting impaired feedback
• Can occur in older adults, but in children more frequently

Question 20

Types of Craniopharyngioma

Answer 20

• ACPS
  
  • Driven by a certain mutation that effects the beta katanin stability – appear very systic in nature
• PCPs
  
  • Present in older adult
  • Due to mutation + lead to solid tumours

Question 22

Prader-Willi syndrome

Answer 22

• Genetic disorder
• 7 genes on chromosome 15 are deleted or unexpressed
• Incidence 1/10-25,000
• People with this condition are obese, have reduced muscle tone and mental ability, and have sex glands that produce little or no hormones.

Question 23

Genetic Mutation - Paternal Linked

Answer 23

• Caused by a lack of active genetic material in a particular region of chromosome 15
• 1 chromosome from mom, one from dad
• Genes are active on the chromosome that comes from the father
• The genetics defect comes from the father and can occur in 1 of 3 ways:

1. because part of the chromosome 15 from the father is either missing or deleted – 70% of cases
2. occurs when an individual inherits two chromosomes from the mother and none from the father – 30% of cases
3. Rare –small genetic mutation in the region of chromosome 15 – genetic general is present but is not active – metalation defect – 1 0r 2% of individuals

Question 24

Prader-Willi syndrome - Pathophysiology

Answer 24

• Poor muscle tone
• Intense cravings for food
• Uncontrollable weight gain
• Obesity leads to lung failure, right A-V failure
• Abnormal glucose tolerance
• High insulin levels
• High CO2
• Low O2

Question 25

Disease Management

Answer 25

• Currently no cure
• Community management of food intake
• Exercise to increase LBM
• GH to improve physical strength
• Males treated with testosterone
• Adolescents treated with HRT

Question 26

Turner Syndrome

Answer 26

• Turner syndrome is a genetic condition in which a female does not have the usual pair of two X chromosomes.
• Monosomy X – Random Event
• Incidence 1 / 2000 live births
• Results one one normal x chromosome, the other chromosome is missing or altered
• Effects development before and after birth
• Monosomy x = the individual has only one copy of the sex chromosomes instead of 2
• Abnormality occurs at a random event during the formation of reproduction cell (egg + sperm) in the effective persons parent – error in cell division cell dysfunction resulting in an abnormal # of chromosomes

Question 27

Stymptoms of Turner Syndrome

Answer 27

• Wide / webbed neck
• Swollen hands and feet
• Absent pubertal development unless they receive hormone therapy
• Drooping eyelids
• Dry eyes
• Infertility
• Short height
• Obesity / Diabetes