Chemiosmotic Theory - Importance (5 Marks)

1. Explains the Mechanism of Oxidative Phosphorylation

• Harper's Illustrated Biochemistry, 32nd Ed

2. Establishes H⁺ Gradient as the Common Energy Intermediate

• Lippincott's Illustrated Reviews: Biochemistry, 8th Ed

3. Accounts for the Function of ATP Synthase (Complex V)

• Lippincott's Illustrated Reviews: Biochemistry, 8th Ed

4. Explains Respiratory Control and the Role of Uncouplers

• Harper's Illustrated Biochemistry, 32nd Ed

5. Universal Applicability - Mitochondria, Chloroplasts, and Bacteria

Summary Table

High Energy Compounds - With Reference to ATP and Creatine Phosphate

Definition

High-energy bonds are "unstable," and their hydrolysis yields substantial free energy because the products are much more stable as a result of electron resonance within their structures.

• Basic Medical Biochemistry, 6th Ed

Classes of High Energy Compounds

• Harper's Illustrated Biochemistry, 32nd Ed (Table 11-1)

ATP - The Energy Currency of the Cell

Structure

Why is the ΔG of Hydrolysis So High?

1. Electrostatic repulsion relief - breaking the terminal P-O bond relieves strong repulsion between the four negatively charged oxygen atoms in the adjacent phosphate groups.
2. Resonance stabilization - the released orthophosphate (Pi) forms resonance hybrids where three negative charges are shared among four oxygen atoms, making the products far more stable than ATP.
3. These effects more than compensate for the initial energy needed to break the bond, resulting in the large negative ΔG.

• Harper's Illustrated Biochemistry, 32nd Ed (Figure 11-5)

ATP as Intermediate Energy Carrier

• Compounds above ATP (e.g., PEP, creatine phosphate) can donate ~P to ADP to regenerate ATP
• ATP can donate ~P to compounds below it (e.g., glucose → glucose-6-phosphate) to drive biosynthetic reactions
• This intermediate position makes ATP a versatile phosphate donor and acceptor

ATP/ADP Cycle

• Harper's Illustrated Biochemistry, 32nd Ed

Sources of ATP

1. Oxidative phosphorylation - the greatest quantitative source; generates ATP in mitochondria as O₂ is reduced via the respiratory chain
2. Glycolysis - net 2 ATP per glucose (substrate-level phosphorylation via phosphoglycerate kinase and pyruvate kinase)
3. Citric acid cycle - 1 GTP per turn (succinate thiokinase step)

Creatine Phosphate (Phosphocreatine) - The Phosphagen

Nature

Location

• Vertebrate skeletal muscle (most abundant)
• Heart muscle
• Brain
• Spermatozoa

Role 1 - Immediate Energy Reserve

Creatine phosphate + ADP ⇌ Creatine + ATP (catalyzed by creatine kinase)

• Harper's Illustrated Biochemistry, 32nd Ed

Role 2 - The Creatine Phosphate Shuttle

• Mitochondrial creatine kinase (CKm) in the intermembrane space transfers high-energy phosphate from newly synthesized ATP (emerging from the adenine nucleotide transporter) to creatine, forming creatine phosphate
• Creatine phosphate is transported out via protein pores in the outer mitochondrial membrane into the cytosol
• In the cytosol, creatine kinase regenerates ATP from creatine phosphate + ADP at the site of energy utilization (e.g., myofibrils)
• This system allows rapid spatial transfer of high-energy phosphate from mitochondria to the cytoplasm
• Harper's Illustrated Biochemistry, 32nd Ed (Figure 13-14)

ATP is Not Stored in Quantity - Why Creatine Phosphate is Needed

• Basic Medical Biochemistry, 6th Ed

Creatinine - Clinical Relevance

Comparison Summary: ATP vs Creatine Phosphate

Part 1: Why are p53 Mutations Found in ~50% of Human Cancers?

p53 - Guardian of the Genome

What is p53?

1. Activation of temporary cell cycle arrest (quiescence) - allowing time for DNA repair
2. Induction of permanent cell cycle arrest (senescence)
3. Triggering of programmed cell death (apoptosis)

"If RB is a sensor of external signals, p53 can be viewed as a monitor of internal stress, directing stressed cells toward one of these pathways."

• Robbins & Kumar Basic Pathology

Normal p53 Regulation - The MDM2 Connection

• Increases p53's half-life dramatically
• Enhances its transcriptional activity
• Allows it to activate hundreds of target genes

p53 Downstream Actions - Why Loss is So Catastrophic

• Oncogene overactivation (unbridled MYC or RAS activity) - triggering ARF, which blocks MDM2
• Anoxia/hypoxia
• Replication stress

Why Mutations in p53 Lead to Cancer So Frequently

• Loss of p53 function means cells with damaged DNA can bypass arrest and continue to divide
• DNA repair does not occur before replication - mutations are propagated
• Apoptosis is not triggered - genetically damaged cells survive
• The cell accumulates further mutations unopposed, a process called genomic instability

• Robbins & Kumar Basic Pathology; Cummings Otolaryngology; Basic Medical Biochemistry 6th Ed

Part 2: Carcinogenic Agents

A. Chemical Carcinogens

1. Direct-Acting Agents

• Alkylating agents (nitrogen mustard, cyclophosphamide) - used in cancer chemotherapy but can themselves cause secondary malignancies (e.g., leukemia after treatment for Hodgkin lymphoma)
• They cross-link or alkylate DNA bases

2. Indirect-Acting Agents (Procarcinogens)

Nitrosamines are consumed in many natural products and produced in the stomach from nitrites used as preservatives. They methylate guanine, and if unrepaired, this introduces a mutation on the next replication cycle.

• Basic Medical Biochemistry, 6th Ed

Initiation-Promotion Model

• Initiation: A mutagen causes a permanent DNA mutation in a cell
• Promotion: Repeated exposure to a promoter (non-mutagenic, non-carcinogenic alone) causes clonal expansion of the initiated cell, leading to tumor development. The promoter must follow initiation repeatedly to be effective.

B. Physical Carcinogens

1. Ionizing Radiation (X-rays, gamma rays, nuclear radiation)

• Causes single- and double-strand DNA breaks, chromosome translocations, deletions
• All forms - electromagnetic (X-ray, gamma) and particulate (alpha, beta, neutrons) - can cause cancer
• Examples: Leukemia in atomic bomb survivors, thyroid cancer from radioiodine, lung cancer in uranium miners (radon)

2. Ultraviolet (UV) Radiation

• UVB (280-320 nm) is the most carcinogenic wavelength
• Causes pyrimidine (thymine) dimers in DNA, repaired by nucleotide excision repair (NER)
• With excessive sun exposure, NER is overwhelmed and damage persists
• Causes squamous cell carcinoma, basal cell carcinoma, and malignant melanoma
• More than 90% of skin cancers occur in sunlight-exposed areas
• Defective NER (as in Xeroderma pigmentosum) causes extreme UV sensitivity and early skin cancer

C. Biological Carcinogens (Viral)

Part 3: Mechanism of Conversion of Proto-oncogene to Oncogene

What are Proto-oncogenes?

Mechanisms of Conversion

1. Point Mutation

• Normal Ras is a GTPase that is active (bound to GTP) transiently and inactivated by hydrolyzing GTP → GDP
• A point mutation at codon 12 (Gly → Val) abolishes GTPase activity
• Result: Ras stays permanently locked in the active GTP-bound state
• Continuously stimulates the MAP kinase proliferation pathway
• Found in ~30% of all human cancers

2. Gene Translocation / Chromosomal Rearrangement

• Burkitt lymphoma: Translocation t(8;14) moves c-myc (chromosome 8) next to the immunoglobulin heavy chain promoter (chromosome 14). c-Myc is now constitutively expressed at high levels in B cells, driving uncontrolled proliferation.
• CML (Philadelphia chromosome): Translocation t(9;22) fuses BCR (chr 22) with ABL (chr 9) proto-oncogene to produce the Bcr-Abl fusion protein. Abl loses its regulatory region and becomes a constitutively active tyrosine kinase, stimulating the Ras/MAP kinase pathway → cell proliferation. This is the target of imatinib (Gleevec).

3. Gene Amplification

• N-myc amplification in neuroblastoma (poor prognosis marker)
• erb-B2 (HER2/neu) amplification in breast and ovarian carcinoma - the target of trastuzumab (Herceptin)
• Amplification appears cytogenetically as double minutes (extrachromosomal DNA) or homogeneous staining regions (HSRs) on chromosomes

4. Viral Insertion

• An oncogenic retrovirus may integrate a viral oncogene (v-onc) directly into the host genome. v-onc genes are mutated/truncated forms of captured cellular proto-oncogenes that have lost regulatory control.
• Alternatively, a virus may insert a strong viral promoter (LTR sequence) adjacent to a cellular proto-oncogene, causing its overexpression without mutating the gene itself (insertional mutagenesis).

Summary Diagram of Mechanisms

PROTO-ONCOGENE
      │
      ├─── Point mutation (coding region) ──→ Hyperactive oncoprotein
      │
      ├─── Point mutation (regulatory region) ──→ Overexpressed normal protein  
      │
      ├─── Chromosomal translocation ──→ New promoter control / Fusion protein
      │
      ├─── Gene amplification ──→ Excess normal protein
      │
      └─── Viral insertion ──→ Viral oncogene / Insertional overexpression
                                        │
                               ONCOGENE (gain-of-function)
                                        │
                        Uncontrolled cell proliferation → CANCER

• Basic Medical Biochemistry, 6th Ed (Figure 17.3); Robbins & Kumar Basic Pathology; Thompson & Thompson Genetics and Genomics in Medicine, 9th Ed

1. Dietary Fiber - Examples, Functions, and Constipation

Definition

Four Examples of Dietary Fiber

Classification

• Dissolves in water to form a viscous gel
• Fermented by colonic bacteria
• Lowers blood cholesterol and glucose

• Does not dissolve in water
• Adds bulk to stool and speeds colonic transit
• Prevents constipation

Functions of Dietary Fiber

1. Laxative Effect / Bowel Regularity

2. Cholesterol Lowering

3. Glycemic Control

4. Prebiotic Effect

5. Protection Against Colorectal Cancer

6. Satiety and Weight Management

7. Reduction of Diverticular Disease

How Dietary Fiber Helps Patients with Constipation

1. Water absorption and stool bulking: Insoluble fiber (cellulose, hemicellulose) is hygroscopic - it absorbs and retains water in the colon, making stools softer, heavier, and easier to pass.
2. Increased fecal mass: A larger, bulkier stool mechanically stimulates stretch receptors in the colonic wall, triggering reflex peristalsis and more frequent defecation.
3. Reduced transit time: By increasing stool bulk and stimulating motility, fiber reduces the time contents spend in the colon (from the normal ~3 days to shorter), preventing excessive water reabsorption and hard stools.
4. SCFA production: Bacterial fermentation of soluble fiber produces SCFAs, which lower colonic pH and also stimulate colonic motility.
5. Osmotic effect: Fermentation products and retained water maintain an osmotic gradient that keeps water in the stool.

2. Protein Energy Malnutrition (PEM)

Definition

Causes

• Primary: Inadequate dietary intake of protein and/or calories (developing countries - children after weaning)
• Secondary: Medical conditions decreasing appetite, malabsorption, trauma, infection, or major surgery (hospitalized patients in developed countries)

Two Extreme Forms

A. Kwashiorkor

• Occurs when protein deprivation is relatively greater than caloric reduction
• Carbohydrate intake may be adequate (child switched to a high-carbohydrate, low-protein diet after weaning, around age 1 year)
• Insulin levels remain elevated → suppresses lipolysis and proteolysis initially
• Severely decreased synthesis of visceral proteins (albumin, transferrin)
• Called "nonadapted" malnutrition

B. Marasmus

• Occurs when calorie deprivation is relatively greater than protein reduction
• Total starvation - both protein and energy deficient
• Body adapts by mobilizing fat stores and muscle (gluconeogenesis)
• Called "adapted" malnutrition

C. Marasmic Kwashiorkor

Comparison Table (Lippincott's Illustrated Reviews, 8th Ed)

Biochemical Features of Kwashiorkor

• Low serum albumin, transferrin, prealbumin
• Decreased VLDL → fatty liver
• Impaired immune function (low IgA, T-cell dysfunction)
• Hypokalemia, hyponatremia

Treatment

• Gradual nutritional rehabilitation (rapid refeeding causes refeeding syndrome - hypophosphatemia as phosphate is consumed by phosphorylating carbohydrate intermediates)
• Milk-based feeds (rich in phosphate)
• Correction of electrolytes, micronutrients (zinc, vitamin A)

3. Basal Metabolic Rate (BMR)

Definition

• Units: kcal/day or kJ/day
• Average adult male BMR: ~1600-1800 kcal/day
• Average adult female BMR: ~1200-1400 kcal/day

Measurement

• Harris-Benedict equation (original standard)
• Indirect calorimetry (measuring O₂ consumption and CO₂ production)

Factors Affecting BMR

1. Body Surface Area (BSA) and Body Size

2. Age

3. Sex

• Greater lean body mass (muscle has higher metabolic rate than fat)
• Testosterone promotes muscle mass and metabolic rate

4. Thyroid Hormones

• Hyperthyroidism → markedly elevated BMR (up to +80%)
• Hypothyroidism → significantly decreased BMR (down to -40%)
• Thyroid hormones increase expression of Na⁺/K⁺-ATPase, mitochondrial uncoupling proteins, and oxidative metabolism

5. Body Composition (Lean Body Mass)

6. Nutritional State

• Prolonged starvation or caloric restriction → BMR decreases (metabolic adaptation to conserve energy)
• Overfeeding → slight increase in BMR (diet-induced thermogenesis)

7. Temperature

• Fever increases BMR by approximately 13% per 1°C rise in body temperature
• Cold environmental temperature increases BMR due to increased thermogenesis (shivering and non-shivering thermogenesis)

8. Hormones

• Adrenaline (epinephrine): Acutely increases BMR (fight or flight response)
• Growth hormone: Increases lean body mass → increases BMR
• Insulin: Promotes anabolism but does not directly raise BMR
• Sex hormones: Androgens increase BMR; estrogens have less effect

9. Pregnancy and Lactation

10. Drugs

• Stimulants (caffeine, sympathomimetics) increase BMR
• Beta-blockers decrease BMR
• Anesthetics decrease BMR

4. Metabolic Syndrome and Cardiovascular Disease Risk

Definition

Diagnostic Criteria (NCEP ATP III - at least 3 of 5)

1. Abdominal obesity: Waist circumference >40 inches (>102 cm) in men; >35 inches (>88 cm) in women
2. Elevated triglycerides: ≥150 mg/dL
3. Reduced HDL cholesterol: <40 mg/dL (men), <50 mg/dL (women)
4. Elevated blood pressure: ≥130/85 mmHg
5. Elevated fasting glucose: ≥100 mg/dL

Why Metabolic Syndrome Increases CVD Risk

1. Insulin Resistance → Hyperglycemia → Endothelial Damage

• Insulin resistance impairs glucose uptake in muscle and fat, leading to hyperglycemia
• Advanced glycation end-products (AGEs) from glycated proteins cross-link collagen in vessel walls, reducing elasticity
• Hyperglycemia generates reactive oxygen species (ROS) that damage endothelial cells, initiating the atherosclerotic process

2. Dyslipidemia (Atherogenic Lipid Profile)

• Insulin resistance increases free fatty acid (FFA) flux to the liver → increased hepatic VLDL synthesis → hypertriglyceridemia
• Elevated triglycerides promote exchange of triglycerides for cholesterol esters in HDL (via CETP) → HDL becomes triglyceride-rich and is rapidly cleared → low HDL
• Small, dense LDL particles are produced (more atherogenic than large LDL - penetrate endothelium more easily, more susceptible to oxidation)

3. Hypertension → Mechanical Endothelial Stress

• Increased circulating FFAs activate the renin-angiotensin-aldosterone system
• Insulin resistance reduces nitric oxide (NO) bioavailability (impaired vasodilation)
• High blood pressure mechanically damages the endothelium and promotes foam cell formation in arterial walls

4. Visceral Adiposity → Pro-inflammatory and Pro-thrombotic State

• Visceral (abdominal) fat is metabolically active and secretes pro-inflammatory adipokines:
  • TNF-α, IL-6 → systemic inflammation → CRP elevation → promotes plaque instability
  • Decreased adiponectin → increased insulin resistance and pro-atherogenic effects
  • Increased PAI-1 (plasminogen activator inhibitor-1) → impaired fibrinolysis → pro-thrombotic state
• Elevated CRP and fibrinogen increase risk of acute thrombotic events (MI, stroke)

5. Progression to Type 2 Diabetes

• Insulin resistance predisposes to frank type 2 DM
• Diabetes itself is a major independent risk factor for CVD (2-4x increased risk), accelerating atherosclerosis, autonomic neuropathy, and renal disease

"A major adverse consequence of the metabolic syndrome is cardiovascular disease, including atherosclerosis and injury to various organs throughout the body. Several of the metabolic abnormalities associated with the syndrome increase the risk for cardiovascular disease, and insulin resistance predisposes to the development of type 2 diabetes mellitus, which is also a major cause of cardiovascular disease."

• Guyton and Hall Textbook of Medical Physiology

5. Glycemic Index (GI) and Its Significance

Definition

GI = (Area under blood glucose curve for test food ÷ Area under blood glucose curve for reference food) × 100

Classification

Factors That Affect GI

1. Degree of processing: Refined/processed foods have higher GI (grinding destroys fiber matrix)
2. Fiber content: High fiber slows glucose absorption → lower GI
3. Starch structure: Amylose (straight chain) has lower GI than amylopectin (branched); resistant starch has very low GI
4. Ripeness of fruit: Riper fruit = higher GI (more simple sugars)
5. Fat and protein content: Slow gastric emptying → lower GI
6. Cooking method: Overcooking gelatinizes starch → higher GI
7. Acidity: Vinegar/lemon juice lowers GI (slows gastric emptying)
8. Particle size: Coarsely ground grains have lower GI than finely ground

Glycemic Load (GL)

Significance of Glycemic Index

1. Diabetes Management

• Low GI foods produce a smaller, more gradual rise in blood glucose, reducing postprandial hyperglycemia
• Reduces demands on insulin secretion
• Low GI diets improve HbA1c levels in type 2 diabetics
• High-fiber, low-GI diets are a cornerstone of diabetes dietary management

2. Weight Management and Obesity Prevention

• Low GI foods promote satiety (slower digestion, sustained energy release)
• Reduce hunger and caloric intake
• High GI foods cause rapid glucose spike → rapid insulin surge → hypoglycemia 2 hours later → rebound hunger and overeating

3. Cardiovascular Disease Prevention

• Low GI diets reduce postprandial triglycerides and improve HDL cholesterol
• High GI diets elevate triglycerides and promote atherogenesis

4. Prevention of Type 2 Diabetes

• Chronically high GI diets cause repeated large insulin surges → beta-cell exhaustion → insulin resistance → progression to type 2 DM

5. Athletic Performance

• High GI foods before/during intense exercise provide rapid glucose for immediate energy
• Low GI foods before endurance events provide sustained energy release

6. Cancer Risk

• Some evidence that high GI/GL diets promote insulin-like growth factor (IGF-1) signaling, which may promote certain cancers (colorectal, breast)

6. Nitrogen Balance

Definition

Nitrogen Balance = N intake - N output

• Grams of protein = grams of nitrogen × 6.25

Types of Nitrogen Balance

A. Nitrogen Equilibrium (Zero Balance)

• N intake = N output
• Seen in healthy adults with adequate nutrition
• Protein synthesis = protein breakdown

B. Positive Nitrogen Balance (N intake > N output)

• Growing children (rapid protein accretion in muscle, bone)
• Pregnancy (fetal and maternal tissue growth)
• Recovery from illness or surgery (tissue repair)
• Athletes in training (muscle hypertrophy)
• Convalescence after malnutrition or trauma
• Treatment with anabolic steroids or growth hormone

C. Negative Nitrogen Balance (N intake < N output)

• Starvation or inadequate protein intake (protein used for gluconeogenesis)
• Severe infections, sepsis, trauma, burns (hypercatabolic states)
• Major surgery
• Fever (increased metabolic rate)
• Malignancy (cancer cachexia)
• Immobilization (disuse atrophy)
• Cushing syndrome (excess cortisol → protein catabolism)
• Elderly (declining anabolic hormones, poor intake)

Factors Affecting Nitrogen Balance

1. Dietary Protein Intake (Quantity and Quality)

• Adequate protein and calories are essential for nitrogen equilibrium
• Complete proteins (containing all essential amino acids - animal proteins) are more efficient at maintaining N balance
• Incomplete proteins (lacking one or more essential amino acids) lead to negative N balance even if total protein intake appears adequate

2. Total Calorie (Energy) Intake

• Carbohydrate is protein-sparing: if caloric intake from carbohydrate/fat is adequate, amino acids are not diverted to gluconeogenesis
• If calorie intake is inadequate (even with sufficient protein), amino acids are catabolized for energy → negative N balance
• Every gram of protein requires adequate calories to be utilized for anabolism

3. Physiological State

• Growth, pregnancy, lactation → positive balance
• Age → older adults require higher protein intake to maintain equilibrium (reduced anabolic response to dietary protein)

4. Hormonal Influences

• Anabolic hormones (insulin, testosterone, GH, IGF-1) → promote protein synthesis → positive N balance
• Catabolic hormones (cortisol, glucagon, epinephrine) → promote protein breakdown → negative N balance
• Thyroid hormones: physiological levels support protein synthesis; excess causes protein catabolism

5. Physical Activity

• Resistance/endurance exercise → stimulates muscle protein synthesis → promotes positive balance (especially with adequate protein intake)
• Immobilization → muscle atrophy → negative balance

6. Disease and Stress States

• Trauma, surgery, burns, sepsis → massive protein catabolism (stress hormones) → strongly negative balance
• Inflammation releases cytokines (IL-1, TNF-α) that promote proteolysis

7. Digestibility and Biological Value of Protein

• Biological value (BV) = proportion of absorbed protein retained (not excreted)
• Egg white has BV = 100 (reference); milk ~91, beef ~80, wheat ~64, soy ~74
• Low BV proteins → more urinary nitrogen for same intake → harder to maintain balance

7. Obesity - Diseases, and Assessment

Definition

Assessment of Obesity

1. Body Mass Index (BMI)

BMI = Weight (kg) ÷ Height (m²)

Note: BMI does not distinguish fat from muscle mass. A muscular athlete may have a high BMI without being obese. BMI thresholds for Asian populations are lower (overweight ≥23, obese ≥27.5).

2. Waist Circumference (Central/Abdominal Obesity)

• More specifically predicts visceral fat and metabolic risk than BMI
• Risk increases significantly with:
  • Men: Waist >40 inches (>102 cm)
  • Women: Waist >35 inches (>88 cm)
• Central/visceral obesity is more dangerous than peripheral (gluteal/subcutaneous) obesity

3. Waist-to-Hip Ratio (WHR)

• WHR >0.9 (men) or >0.85 (women) indicates central obesity
• Strongly associated with cardiovascular and metabolic risk

4. Body Fat Percentage

• Measured by DEXA scan (gold standard), skinfold calipers, bioelectrical impedance
• Obesity: >25% body fat (men), >35% (women)

5. Waist-to-Height Ratio

• Waist/height >0.5 indicates increased cardiometabolic risk
• Simple, practical tool across all ages and ethnicities

Diseases Related to Obesity

1. Cardiovascular Disease

• Obesity (especially visceral) → insulin resistance → metabolic syndrome → hypertension, dyslipidemia, atherosclerosis
• Increased cardiac workload → left ventricular hypertrophy → heart failure
• Risk of coronary artery disease, stroke, and sudden cardiac death all elevated

2. Type 2 Diabetes Mellitus

• The single most important risk factor for T2DM
• Visceral adiposity → increased circulating FFAs → lipotoxicity in muscle and liver → insulin resistance
• Adipokine dysregulation (decreased adiponectin, increased TNF-α) worsens insulin signaling
• Approximately 80-90% of T2DM patients are overweight or obese

3. Non-Alcoholic Fatty Liver Disease (NAFLD) / NASH

• Excess FFAs → hepatic triglyceride accumulation → fatty liver (steatosis)
• Can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma

4. Obstructive Sleep Apnea (OSA)

• Excess fat around pharynx → airway obstruction during sleep → repeated apneic episodes
• Leads to daytime somnolence, hypertension, pulmonary hypertension, right heart failure

5. Osteoarthritis

• Excess mechanical load on weight-bearing joints (knees, hips)
• Adipokines from fat also have direct pro-inflammatory effects on cartilage

6. Cancers

• Obesity associated with increased risk of: endometrial, breast (post-menopausal), colorectal, esophageal, pancreatic, kidney, gallbladder cancers
• Mechanisms: hyperinsulinemia/IGF-1 signaling, excess estrogen (adipose aromatase), chronic inflammation

7. Polycystic Ovary Syndrome (PCOS)

• Obesity → hyperinsulinemia → stimulates ovarian androgen production → PCOS
• Leads to infertility, hirsutism, menstrual irregularity, and further cardiovascular risk

8. Gallstones (Cholelithiasis)

• Obesity → increased hepatic cholesterol synthesis and secretion into bile → supersaturation → cholesterol gallstones
• Risk increases by 2-3x with obesity

9. Hypertension

• Increased circulating volume, sympathetic activation, RAAS stimulation, and mechanical factors all contribute
• Present in >70% of obese individuals

10. Respiratory Problems

• Pickwickian syndrome (obesity hypoventilation syndrome) - obesity causes restricted lung expansion → chronic hypoxia and hypercapnia

Summary of Diseases Related to Obesity

                     OBESITY
                        │
    ┌───────────────────┼───────────────────┐
    │                   │                   │
Metabolic           Mechanical          Inflammatory
    │                   │                   │
T2DM               Osteoarthritis       NAFLD/NASH
Dyslipidemia        OSA                 Cancer
Hypertension        Back pain           PCOS
CVD/Atherosclerosis Gallstones