14 - Obesity & Lifespan

Obesity: Biologic, Environmental & Social Factors

• Environmental and societal factors 

  • Media

  • Policies

  • Work schedules

  • Food availability 

• Biological factors 

  • Genetics and epigenetics

  • Internal clocks

  • Inflammation

  • Physiological circuitry (adipocytes, disruptions in metabolism)

Health Risks of obesity (BMI > 30)

• ↑ All-cause mortality

• Hypertension

• Dyslipidemia (↑ LDL, ↓ HDL, ↑ triglycerides)

• Type 2 diabetes mellitus (T2DM)

• Coronary heart disease (ASCVD)

• Cerebrovascular accident (CVA/stroke)

• Gallbladder disease (cholecystitis)

• Osteoarthritis

• Body pain & difficulty with physical functioning

• Obstructive sleep apnea (OSA)

• Cancer (figure)

• Mental health issues (e.g., depression & anxiety)

• ↓ health-related quality of life (HR-QoL)

Obesity complications: Adult

• Depression

• Increased risk of stroke

• Pulmonary embolisms/HTN

• GI (gallbladder, pancreatitis)

• T2DM

• Impaired reproduction

Obesity complications: pediatric

• Psychosocial (eating disorders, depression, self-esteem)

• GI issues 

• Endocrine (hypogonadism, PCOS, precocious puberty)

• Asthma, exercise intolerance

• Musculoskeletal effects 

sites of adipogenesis

• Two key niches: subcutaneous & visceral 

• Subcutaneous adipose tissue: 

  • white fat 

  • Insulating and energy storage location

• Visceral adipose tissue 

  • Result of excess nutrition, excess glucose (e.g. large meal) → fat storage → lipogenesis 

  • Signals = insulin and glucocorticoids 

• Bone marrow = formation of RBCs and other hematopoietic functions 

• Most sensitive adipose tissue = muscle 

  • Normally muscle is insulin sensitive and processes glucose regularly 

  • Intramyocellular lipo deposits → insulin resistance (in obesity)

    • Fat deposits in the muscle = hallmark of rising insulin resistance 

adipose tissue

• specialized type of connective tissue

• originate from mesenchymal stem cells (fetal development)

• comprised of adipocytes (cells that store lipids)

• accounts for 20–25% of total body weight in healthy adults

adipose tissue locations

• subcutaneous (throughout body, between skin & muscle)

• visceral fat (surrounding organs) – metabolically unhealthy adipose tissue 

• bone marrow (intra-osseous)

types of adipocytes

• White: a single large lipid droplet, few cellular organelles (lacks mitochondria), most abundant (85%)

• Beige (Brite): scattered among white adipocytes, sometimes generate heat

  • (i.e., in response to cold exposure, adrenergic stimulation)

• Brown: contain many lipid droplets, many mitochondria, generate heat (thermogenesis)

  • (most pronounced in fetal life, metabolically active 2° ↑ mitochondria)

white adipose tissue: hypertrophy

• Hypertrophy

  • formation of a few large adipocytes

  • accumulation of lipids in existing cells (get increasingly filled with lipids)

  • Hypertrophy →

    • Impaired lipolysis (breakdown of fat cells into energy)

    • Impaired lipid synthesis

    • Impaired endocrine function

    • Hypoxia → cell damage

    • Activates immune system and inflammation

      • Contributes to metabolic disruption (insulin resistance, T2DM, HTN)

  • More worried about hypertrophy (fat cells getting enlarged) than hyperplasia!

white adipose tissue: hyperplasia

• precursor cells proliferate & differentiate into many small adipocytes

  • Normal adipocyte function

  • Normal stromal function (undergo lipolysis when they are signaled to)

  • Result in benign effects 

endocrine functions of (white) adipose tissue

• WAT: Lectin and Adiponectin 

  • Key metabolic effects 

  • Lectin: decreases appetite, thermoregulation, glucose homeostasis 

  • In pancreas: both have roles in insulin secretion and beta cell survival 

  • CV function: both have roles in inflammation, vascular remodeling, perivascular fat deposits 

  • Liver: adiponectin has key role in glucose metabolism, lipid metabolism, insulin signaling, gluconeogenesis

  • Muscle: adiponectin has key role in glucose metabolism, lipid metabolism, insulin signaling

adipokines

• Adipokines = products released by adipocytes (WAT and BAT)

• WAT & BAT secrete products in response to AT energy status

  • Stores of energy; when they are signaled, they release their products 

  • Peptide hormones (adipokines), bioactive lipids (lipokines), & RNA molecules

  • Local (paracrine) & systemic (endocrine) effects (brain, β-cells, liver, skeletal muscle, & CV system)

  • Regulate key functions (appetite, thermogenesis, glucose & lipid metabolism)

  • Inactivity, no cold/excess heat, caloric excess → WAT sends signals to make hypertrophic adipocytes 

    • Results in high saturated FFAs, leptin, decreased adiponectin 

adipokines: healthy state

• organ function

• metabolic homeostasis

• Low FFAs, low leptin, high adiponectins 

adipokines: obesity

• chronic, proinflammatory state (exacerbating cardiometabolic disease)

• Shift towards hypertrophic WAT

  • Contribute to pro-inflammatory state

  • Increased leptin, decreased adiponectin 

adipose tissue & inflammation: HEALTHY person

• Intake > expenditure (nutrients/calories)

• Healthy storage (perivascular preadipocyte) 

• Undergo hyperplasia (NOT hypertrophy)

• Increase in weight, but still metabolically healthy 

  • Beneficially adipokines coming from hyperplasia will be FGF21 (stimulates energy regulation)

  • Leptin and adiponectin suppresses food intake and promotes lipolysis 

adipose tissue & inflammation: UNHEALTHY person

• Intake > expenditure 

• Unhealthy storage (hypertrophy)

• Deposits of collagen, macrophages, inflammation (hypoxia, necrosis)

• Activates immune system and chronic inflammation 

• Ectopic lipid deposits (on viscera) and adipose tissue dysfunction (intramyolar - muscle deposits)

  • Deposits in organs and muscles → lose insulin sensitivity 

• Increase levels of glucose and lipids in circulation

• Metabolically unhealthy 

Leptin

• WAT produces leptin (pro-inflammatory immune function) 

  • Leptin suppresses food intake and promotes lipolysis (breaks down WAT and liberating energy)

    • Problemating when you have enough glucose in circulation 

  • Normally Leptin receptors (in brain) inhibit food intake and adrenal production of steroids 

    • Also has effects on stimulating growth, energy expenditure, glycemic control, and reproduction 

Adiponectin

• Adiponectin

  • Effects on the brain (energy expenditure, hormone secretion)

  • Liver: lipid and glucose metabolism, insulin sensitivity 

  • Pancreas: insulin sensitizer – key role in lipid and glucagon secretion (gluconeogenesis), promotes beta cell survival (limits progression of prediabetes → diabetes)

  • Blood vessels: promotes angiogenesis 

  • Immune cells: anti-inflammatory effects 

adipocytes & inflammation: lean person with noraml metabolic function

• Lean person with normal metabolic function

  • inflammation, metabolic control, and vascular function are all normal 

  • Some infiltration of (M2) macrophages, T cell (CD4) (normal)

  • No issue producing anti-inflammatory adipokines (adiponectin)

adipocytes & inflammation: obese person with mild metabolic dysfunction

• Obese with mild metabolic dysfunction

  • rise in inflammation, decrease in metabolic control, intact vascular function 

  • More infiltration of T cells (CD8) and macrophages 

  • Can still produce adiponectin, but also have pro-inflammatory adipokines (Leptin and IL-6)

    • Due to CD8 T cells and M1 macrophages 

adipocytes & inflammation: obese person with FULL metabolic dysfunction

• Obese with full metabolic dysfunction 

  • Increased inflammation, decreased metabolic control, decreased vascular function (from inflammation around vasculature)

  • Significant inflammation (lots of necrotic adipocytes signaling immune system to bring immune cells in)

  • High inflammation contributes to fibrotic development

  • Increase production of pro-inflammatory adipokines (leptin and IL-6), decreased production of adiponectin (no insulin sensitizing effect)

intramuscular adipose tissue: insulin resistance

• White adipose tissue deposited in muscle

• When WAT is activated to have lipolysis → produce FFAs → bioactive lipids 

• Inflammation if it progresses to insulin resistance and diabetes 

  • Fibrosis and adipocytes 

• Progressive rise in inflammatory cytokines 

  • Proliferation of FFAs (from insulin resistance) 

• Decreased muscle insulin sensitivity (adipocytes not insulin sensitive)

• Hypertrophy of adipocytes

• Lose function of muscle 

reproductive endocrine axis: male

• Testosterone (T) (anabolic & androgenic)

  • growth acceleration

  • ↑ muscle mass

  • penile growth

  • deepening voice

  • virilization

• Estradiol (E2)

  • skeletal maturation

  • Gynecomastia

• LH stimulates Leydig cells to produce testosterone 

• FSH stimulates sertoli cells 

reproductive axis: female

• Estradiol (E2)

  • breast development

  • growth acceleration

  • skeletal maturation

• E2 + progesterone → menstruation

• LH stimulates theca cells 

• FSH stimulates granulosa cells 

puberty: HPG axis activation (males and females)

• Puberty – process culminating in reproductive capacity

• Females: begins ∼ 8-9 yrs. → thelarche (1st sign = breast development) (Tanner 2)

  • complete = 1st ovulatory cycle

• Males: begins ∼ 11 years (1st sign = testicular growth)

  • complete = 1st ejaculation with mature sperm

precocious puberty

• Rare: F>M (1:10,000 girls, <1:50,000 boys)

• Girls → Sexual maturation before 6 - 7 yo

• Boys → Sexual maturation before 9 yo

• Partial & complete forms (Tx=GnRH agonists)

  • Sits on receptor to shut down system 

• Causes:

  • CNS: NL but premature HPG axis activation

  • Extra-CNS: Sex hormones produced by mechanism other than gonadotropin stimulation

    • adrenal hyperplasia (producing weak androgens)

    • gonadal tumors

    • exogenous sex steroid (e.g. male taking gel testosterone replacement and picking up infant and transferring it to the infant) 

delayed puberty

• Common: statistically defined (i.e. 2.5%); M>F

• Boys → No testicular growth (testicular volume <4mL) at 14yo

• Girls → No breast growth (Tanner I) by 13yo or no menarche (1st menses) by 15 yo

• Causes: 

  • Physiologic:

    • constitutional delay of growth & puberty (cause of DP in 2/3 males, 1/3 females) (can be genetic)

  • Pathologic:

    • Functional (malabsorption (e.g. Celiac), anorexia (energy deficit), chronic illness (e.g. Sickle Cell or CF))

    • CNS tumors

hypogonadism: testosterone deficiency

• Testosterone (T)

  • bound T = 98% (bound to SHBG)

  • free T = 2%

• Altered SHBG:

  • Aging (↑)

  • Obesity (↓

  • insulin resistance (↓)

  • liver disease (↑)

  • Inhibits GnRH secretion → decreased testosterone production

• Primary hypogonadism: problem with testes itself (normal gonadotropin but low testosterone)

  • HYPERgonadotropic HYPOgonadism 

• Secondary hypogonadism: problem with neuro-endocrine component (lacking GnRH or pituitary release of gonadotropins → low testosterone) 

  • HYPOgonadotropic HYPOgonadism

timing of onset determines presentation (neonatal vs adolescence)

neonatal:

• micropenis

• cryptorchidism

adolescence

• absent secondary sex characteristics

• small testes/genitalia

• gynecomastia

• eunuchoidal proportions (long limbs)

adulthood

• decreased libido

• sexuald dysfunction

• infertility

• anemia

menopause: Physiology

• Affected by genetic factors, environment, lifestyle, and systemic diseases 

• Changes in neuroendocrine component 

  • Loss of regular pulsatory secretion of GnRH 

  • Impaired timing of LH surging (which usually happens before ovulation)

  • Results in fluctuating estradiol levels 

  • Decline in AMH and inhibin B → increase in FSH (not developing a dominant follicle and not ovulating it)

  • End result: anovulatory cycles and eventual complete loss of menstrual cycle  

• Menopause = 1 year no menses

  • ↓ ovarian reserve

  • FSH ↑ & E2 ↓

  • levels stabilize ∼2 yrs. s/p final menstrual period

• Normally: in follicular phase, there’s slow GnRH pulses → favors FSH secretion

  • Rising estradiol levels, then peak of LH (ovulation)

  • Estradiol falls, inhibin B mirrors estradiol 

• Menopause: variable levels of estradiol

  • Inhibin B falls

  • FSH increases (trying to stimulate follicles)

  • LH increases 

  • Activation of neuroendocrine component to try to drive ovarian development of follicles but failing because of AMH (?)  

• peri-menopause can last between 7-14 years

• menopause is NOT a pathologic state

calcium and phosphate homeostasis

• liver: vitamin D → 25(OH)D

• kidneys: 25(OH)D → 1,25(OH)2D

→ ↑ Ca++ & P absorption (from the gut)

• parathyroid: PTH

→ ↑ Ca++ resorption (reabsorbed from bone)

(when Ca levels are low, reabsorbs Ca from the bone)

→ ↓ Ca++ excretion (kidneys) (wants to hang onto Ca)

→ ↑ P excretion (kidneys)

• thyroid: calcitonin

→ ↓ Ca++ resorption (bone)

→ ↑ Ca++ excretion (kidneys)

• osteocytes: FGF23 

→ ↑ P excretion (kidneys)

→ ↓ 1,25(OH)2D activation

• gonads: estradiol (E2)

→ ↓ resorption (bone)

→ promotes bone formation

key players in bone mineral homeostasis: PTH

1. PTH → ↑ serum Ca++

• ↑ Ca++ resorption from bone (↓ Ca++ triggers osteoclast activity)

• ↑ Ca++ reabsorption in renal tubules

key players in bone mineral homeostasis: calcitonin

1. calcitonin → ↓ serum Ca++

• ↓ osteoclast activity (bone resorption)

• ↓ renal reabsorption

key players in bone mineral homeostasis: 1,25(OH)2D

1. 1,25(OH)2D (kidney) → gut

• ↑ Ca++ & phosphate (P) absorption (to build bone)

• PTH → ↑ 1,25 (OH)2 D

• FGF23 → ↓ 1,25 (OH)2 D

  • Overexpression of FGF23 → osteomalacia)

key players in bone mineral homeostasis: FGF23

1. FGF23 (osteocytes) → act on kidney (Ca++ & P)

• ↓ P resorption → ↓ serum P levels

• ↓ 1,25(OH)2D activation → ↓ Ca++ absorption

• * ↑ FGF23 → osteomalacia

bone remodeling: PTH & 1,25(OH)2D

1. Resorption (calcium from bone)

• PTH stimulates resorption from the bone (osteoclasts break down bone to release Ca)

• RANKL (+) secreted from osteoblasts → ↑ osteoclast action (catabolize/break down bone)

  • RANKL: receptor activator of nuclear factor kappa B ligand (don’t need to know name)

• MCSF (+)

  • → osteoclast differentiation & activation (positive driver of bone catabolism)

  • MCSF: macrophage colony stimulating factor 

• OPG (-)

  • → blocks RANKL (↓ osteoclast activity)

  • OPG: osteoprogerin (inhibitor of RANKL)

2. Formation

• PTH & 1,25 (OH)2D stimulates mesenchymal stem cells → proteoblasts → differentiation to osteoblasts (builds bone)

• PTH → inhibits sclerostin (protein that blocks osteoblast proliferation) 

osteoporosis (+ pathogenesis, diagnosis, prevention)

• Osteoporosis = reduced bone density 

  • (low bone mass & deteriorated microarchitecture)

  • most common metabolic disease

  • 1° = aging vs. 2° = other disorder

• Pathogenesis: imbalance in bone synthesis & resorption

  • osteoclast activity >> osteoblast activity

• Diagnosis = dual X-ray absorptiometry (DXA)

  • osteopenia (T= -1.0 to -1.5) vs. osteoporosis ( T < -2.5)

  • most common fractures: wrist, femur neck, vertebrae (F > M) (role of estradiol in bone building and menopause) 

• Prevention

  • diet high calcium & vitamin D throughout life (supplements)

  • regular weight-bearing exercises: walking

  • weight training stimulates bone mineral density (BMD)

osteoporosis: sex and age

• Sex is a real key driver (falling estradiol)

• Menopause → rapid bone loss (1st phase), slower bone loss (2nd phase)

  • in females

bone remodeling

• (+) RANKL → ↑ osteoclast

• (+) MCSF → ↑ osteoclast

• (-) OPG → ↓ osteoclast

• Osteoblast → bone formation (WNT signaling)

• sclerostin (from osteoclasts) → inhibits bone formation by inhibition of WNT signaling

  • Drive osteoclasts to break down bone to increase Ca levels 

  • At the same time, releases sclerostin to inhibit bone formation (don’t want to take Ca from circulation to build bone)

• Osteoclast → bone resorption

• Estrogens usually promote bone formation (inhibits the cells that break down bone)

  • Also induces apoptosis of osteoclasts 

  • Inhibits RANKL

  • Inhibits sclerostin 

  • Increases osteoblasts, decrease osteoclast (decreases RANKL)

estrogens & bone remodeling

• Menopause: estrogen falls → decrease in osteoblast activity 

  • (no brake pedal on sclerostin → sclerostin can inhibit signaling)

  • Inhibits bone formation

  • Releases inhibition of RANKL (increased RANKL → increases osteoclasts)

    • Much more bone resorption 

  • Go from bone building → bone loss 

osteoporosis: Prevention & Management

• Vitamin D (800 IU QD), Ca++

• Bisphosphonates

  • bind to bone mineral → ↓ osteoclast activity

    • (osteonecrosis jaw, 5yr ‘drug holiday’)

• Denosumab

  • RANKL monoclonal AB → ↓ osteoclast activity

• Teraparatide

  • N-terminal of PTH → ↑ formation, ↓ resorption of bone 

• ERT/SERMs (estrogen replacement therapy)

• Other drug considerations

  • (+) HCTZ → ↑increases renal Ca++ reabsorption

  • (-) glucocorticoids → ↓ vitamin D activation, ↓ Ca++ absorption

• Lifestyle changes 

  • Avoid weight loss and low BMI

  • Daily physical activity (weight-bearing)

  • Cessation of smoking

“Acquired” Functional Hypogonadism

• Weight loss in obese men → ↑ serum T levels (mitigate the precipitating factor!)

• Symptoms of T deficiency are variable & depend on serum T levels:

  • < 430 ng/dL (< 15 nmol/L) → ↓ libido & vigour

  • < 350 ng/dL (< 12 nmol/L) → ↑ fat mass

  • < 280 ng/dL (< 10 nmol/L) → ↑ risk for MetS & T2DM

  • < 230 ng/dL (< 8 nmol/L → ↑ sexual dysfunction

• Treat (testosterone replacement therapy: TRT) only when:

1. two repeated, unequivocal low AM serum T (<280 ng/dL / 10 nmol/L) measures AND

2. symptoms of hypogonadism (Low sexual desire (libido), Difficult achieving orgasm or diminished intensity, Infrequent morning or nocturnal erection)

• TRT can improve health-related quality of life (psychological, somatic, & sexual)

• TRT replacement (particularly injections in older men)  ↑ risk of erythrocytosis

• TRT does not appear to ↑ prostate risk, questions remain about CV & metabolic effects