Chapter 23: Metabolism

Absorptive state - “nutrient-replete”; high blood sugar supply and high insulin (pushes sugar into cells to be metabolized); 0-4 hrs post eating

• Amino acids - absorbed by small intestine and sent to body through the hepatic portal (blood vessels to liver); liver passes them to body for fuel/raw materials and converts excess to fat

• Carbohydrates/sugars - absorbed by small intestine and sent through hepatic portal; liver uses as fuel and delivers to body; excess stored as fat

  • glycogen storage - muscles for quickly-accessible stores and liver to support blood sugar

• Triglycerides (fats) - Not water soluble; broken down to fatty acids and glycerol and absorbed by intestine; then rebuilt into low density lipoproteins (chylomicrons) and enter interstitial fluid to travel through lymph (NOT blood) to muscles or other metabolically active tissue; excess stored in adipose tissue or liver

• Adipose tissue - takes up blood sugar and chylomicrons to store as fat; the two-carbon metabolite of glucose (acetyl-CoA) is building block for fat

  • triglyceride synthesis material sources: 1) fatty acids/glycerol from digestive uptake; 2) excess fat from liver (transported by VLDL and broken down into fatty acids/glycerol); 3) carbon skeletons and energy from glucose catabolism

• insulin - decreases blood sugar by increasing transport of sugar into metabolically active cells; stimulates catabolism of glucose and anabolism of fat; stimulate protein anabolism and aa transport into cell

  • high blood sugar; digestive hormones; PaANS stimulation; increased plasma amino acids

  • Type I diabetes - genetic hyposecretion of insulin (treated with exogenous insulin)

  • Type II diabetes - metabolic dysregulation of insulin; poor diet and sedentary lifestyle (exacerbated by genetics, obesity, etc.)

    • chronically high blood sugar → insulin resistance → positive feedback loop to release more insulin → cells do not have access to fuel and the osmolarity of blood increases (damage tissue and fluid dysregulation)

    • high sugar in urine, body is essentially starving

    • gestational diabetes = developed during or because of hormones from pregnancy

Post-absorptive state - “nutrient-depleted”; low blood sugar supply (need to release from glycogen in liver or catabolize fat); glucagon regulates blood sugar; 4+ hrs after eating

• Four sources: liver glycogen, muscle glycogen/cori cycle, liver gluconeogenesis, protein catabolism

• liver - glycogen breakdown and gluconeogenesis (powered by fat catabolism) to increase blood sugar

• muscles - in anaerobic conditions glucose is fermented to lactic acid and released into the bloodstream and liver where it is formed back into glucose (powered by fat catabolism) = cori cycle

  • during starvation body will catabolize protein (net-loss)

• glucose sparing - preferential oxidation of fatty acids to preserve glucose stores for the brain (long fast or low-intensity exercise)

• glucagon - stimulated by low blood sugar (inhibited by high levels), stimulates liver to produce/release glucose and adipose tissue to break down fat and release FFA

Hormones

• epinephrine (SyANS) - increase fat mobilization and glycogenolysis to increase fuel availability

• cortisol - synergizes with Epi and glucagon, inhibits protein anabolism (glycogen neutral)

• growth hormone - antagonizes epi and cortisol, favors protein anabolism for growth

• thyroid hormone - T3 favors increased metabolism, increased glucose uptake/use, increased fat breakdown, increase protein anabolism

• testosterone/estrogen - increased protein synthesis/regulator of calcium and fat metabolism (estrogen made by adipose tissues and manages the development and distribution)

Liver

• 1) carb management/metabolism - maintain blood glucose, target of insulin

• 2) fat and cholesterol metabolism/management - lipoprotein cycles

• 3) protein metabolism - nitrogenous waste into urea (synthesizes most proteins in bloodstream)

• 4) vitamin/mineral storage

• 5) metabolize/remove most drugs and toxins (also excess hormones, cholesterol or RBC breakdown products in blood)

Cholesterol/fat

• VLDL (very low density lipoproteins) - produced by liver, contain fat and cholesterol to circulate through bloodstream and deliver to other tissues; chylomicrons are similar, but bigger

• LDL - VLDL stripped of fat, circulating and delivering cholesterol to tissues, “bad cholesterol”

• HDL - made in liver, act as sponges to soak up excess cholesterol and deliver to liver (and less potentially clogging arteries), “good cholesterol”

• saturated fat - raises LDL and HDL (found in animal fats), inhibits excretion from body

• cis fats (naturally unsaturated fats) - raise HDL and lower LDL (omega 6 and 3)

• trans fats (processed or partially hydrogenated) - raise LDL and lower HDL, stick in body for longer and contribute to plaque

• atherosclerosis - hardening of arteries, walls are less compliant and less effective at managing blood pressure (positive feedback with hypertension that exacerbate each other)

• atherosclerosis - fatty deposits with excess fat and cholesterol in small arteries (high fat, high LDL, low HDL); fatty macrophages (foam cells) lead to plaque formation that narrows radius (increasing resistance, increasing blood pressure, decreasing flow) or occlude arteries

Hunger/metabolic rate

• established by the arcuate nucleus of the hypothalamus

  • POMC (anorexigenic) - instructs VMN to release CRH and TRH to suppress appetite and increase BMR

  • NPY (orexigenic) - stimulate LHA to release orexins to increase appetite and inhibit actions of VMN

• hormonal controls - insulin (blood sugar), CCK and GLP-1 (digestive system, measuring nutrients), somatostatin (low growth), stretch (PP/PYY), leptin (fat levels)

  • insulin, leptin, CCK downregulate hunger by blocking NPY

  • glucagon, epinephrine, ghrelin (dinner bell) rise during fasting and stimulate appetite

• BMR - basal metabolic rate to stay alive (higher under stress or sick, lower when resting)

• TMR - total metabolic rate, BMR + physical activity

• Body temperature - hypothalamus is thermostat through neurons located in LPO and DMH

  • hypothermia - low body temp (<90), vasoconstriction to extremities, shivering, increased BMR; failure of homeostasis

  • hyperthermia - high body temp (>105), vasodilation, sweating

  • febrile response (fever) - higher homeostatic setpoint by eicosanoid stimulation in the hypothalamus (pyrogens in infectious agents increase inflammatory response); accelerates enzymatic mechanisms, increases blood flow (and WBC recruitment)

    • advil or tylenol are antipyretics and target production of eicosanoid to decrease body temp

Chapter 24/25: Renal System

Kidneys - upper abdominal cavity, 20% of blood flow passes through kidneys; regulation of water and electrolytes, removal of (soluble) waste, gluconeogenesis, endocrine roles (EPO, renin, VitD)

• nephron - functional unit of kidney, ~1 million nephrons/kidney

  

  • tubule - wrap around the renal corpuscle and connect bowman’s capsule with the nephron loop and collecting duct (glomerular ultrafiltrate becomes urine)

  • duct - collect filtrate into ureter

• renal corpuscle = Bowman’s capsule + glomerulus

  

  • glomerulus - blood vessels, fenestrated endothelium forms filtration bed

  • bowman’s capsule - podocytes filter, collection of urinary filtrate

    • gaps between podocytes and fenestrations of endothelium create filtration bed and ultrafiltration of blood at MUCH higher rates than the rest of the body (180-200 L/day)

  • mesangial cells - regulate flow by controlling “tightness” of filtration bed

• afferent and efferent arterioles - carry blood to/from glomerular filtration capillaries (no gas/nutrient exchange, so it is still an arteriole when leaving), maintains high pressure, efferent feeds into peritubular capillaries or vasa recta

• peritubular capillaries - ordinary gas/nutrient exchange in cortex, tubular secretion and absorption

• vasa recta - ordinary gas/nutrient exchange and salt/water exchange (juxtamedullary nephrons)

  • counter current exchanger - permeability of NaCl and water is high, so blood reacts passively to the osmotic and solute gradients established by nephron loop; loses water and gains salt to stay in equilibrium with medulla going down, gains water and loses salt going up; net effect is to reabsorb water and salt and blood volume increases

• juxtaglomerular apparatus - collection of regulatory tissues between distal convoluted tubule (DCT) and arterioles

  • macula densa - specialized part of DCT that “senses” sodium flux and reports it to JG cells as control for urinary flow

  • granular cells - secrete renin (start RAAS) in response to low urinary flux/sodium or SyANS stimulation or drop in blood pressure

  • JG cells - part of the vascular smooth muscle of arterioles, control arteriolar diameter to compensate for pressure changes

Filtration and urine production

• urine filtration

  • glomerular filtration - filtration of bulk fluid through fenestrated endothelium and podocytes (due to hydrostatic pressure), physical basis of urine

    • ultrafiltration through fenestrated endothelium, basement membrane, podocyte epithelium (plasma and solutes can pass but not proteins), driven by overall pressure difference (+10 mmHg)

    • different from ordinary capillaries because there is no gas exchange or reverse filtration in glomerulus, no major drop in pressure

    • GFR (glomerular filtration rate) - amount of plasma filtered into Bowman’s capsule per minute or hour, “renal clearance” to determine chemical filtration (only accurate if it is not reabsorbed, more accurate to use creatinine clearance)

    • Net Filtration Pressure (NFP) is maintained by arteriolar smooth muscle and should be +10 mmHg despite the osmotic imbalance into the blood

  • tubular reabsorption - transport materials from tubules back into capillaries

    • the lack of permeability of kidney tubule and strength of sodium gradient (sodium potassium pump) determines what solutes move where and when

    • PCT - sets basic urine/blood composition

      • nearly complete secretion of toxins or other foreign chemicals (drugs), large amount of reabsorption of materials from urine (nutrients, 65% water and salts, regulated phosphate reabsorption

    • Nephron loop - establishes/maintains hyperosmotic medulla

      • hyperosmolarity generator to power water recovery and urinary volume tuning

      • reduces urine volume; reabsorption of water in descending loop, reabsorption of salt in ascending loop (establishes/maintains hyperosmotic gradient via active Na/K pumps, regulated by aldosterone); secretion of urea in ascending loop and DCT

      • Countercurrent generation -

        • descending loop - concentrates urine 4x by reducing water volume

        • ascending loop - sodium transport into loop allows sodium to enter the medulla, restoring the osmotic strength of the urine to the cortical isosmotic value

        • dehydration - aldosterone increase Na and water recovery into DCT, and urea transport into medulla and water transport into blood

    • DCT/cCD - regulates urine composition

      • regulated reabsorption of salt and water (ALD and AngII), regulated secretion of K⁺ (ALD), regulated reabsorption of Ca⁺² (PTH), regulated secretion of H⁺

    • mCD - regulates urine concentration/volume

      • regulated reabsorption of water (without additional salt, driven by medullary gradient), regulated reabsorption of urea

  • tubular secretion - transport materials out of capillaries to tubules

    • mostly in convoluted tubules (drugs/toxins in PCT; K⁺, H⁺, urea in DCT)

  • excretion - removal of waste from body (urination)

    • detrusor - autonomic muscle surrounding bladder to squeeze out urine, PaANS stimulates contraction when triggered by stretch reflexes

    • internal urethral sphincter - contracts during filling, must relax to pee, stimulated by SyANS stretch reflex on pontine micturition center

    • external urethral sphincter - contracts during filling, must relax to pee, automatic control of pons

    • In general: stretch reflexes activate PaANS to contract detrusor and relax sphincters, while SyANS tone keep sphincters closed

      • conscious action (managed through pontine micturition and pontine storage centers) can intentionally hold or void

      • SyANS involvement explains why you can’t pee while stressed or high levels of stress can induce urination

Controls

• GFR

  • myogenic mechanism - smooth muscle of afferent arteriole contracts or relaxes in response to changing systemic BP to maintain proper pressures

  • tubuloglomerular mechanism - macula densa senses sodium flux through DCT (high sodium means GFR is exceeding reabsorption capacity), triggers afferent arteriole to relax/constrict

  • systemic blood pressure - low BP triggers SyANS vasoconstriction to increase TPR and increase blood volume (RAAS)

    • kidney increases blood volume through increased reabsorption

    • higher sympathetic tone helps GFR through increased BP

      • TG mechanism will keep this under control

• RAAS (renin-angiotensin-aldosterone system)

  • renin - produced by JC in response to tubuloglomerular response, low stretch, local ANGII levels and SyANS; converts ANGogen to ANGI

  • ANGI (angiotensin I) - converted to ANGII and III by ACE and ACE2 enzymes present in heart and lungs

  • ANGII/III - stimulates vasoconstriction and aldosterone release from adrenal cortex

  • aldosterone - stimulated by high K⁺, ACTH stimulation of cortex, low BP (RAAS); leads to increased Na⁺ and therefore water reabsorption

  • ANGII/III mediates vasoconstrictive effects and increases salt/water reabsorption in CCD, stimulates aldosterone

  • ANP - produced by atria upon stretching, negative feedback against excessive BP, inhibits RAAS and ADH, decreases Na⁺ recovered by DCT/cCD

• hydration

  • ANGII (also dry mouth, osmoreceptors and hypothalamus) stimulate hypothalamic thirst centers → signal that body needs more water, decreased blood volume; wet mucous membranes, full stomach induced by water are negative feedback to thirst

  • ADH - stimulated by low BP, high osmolarity of brain stem ECF; ADH-stimulated aquaporins and urea transporters increase water without altering sodium (protection against hypotonic hydration)

  • dehydration - excessive water loss (sweating, diarrhea, blood loss), blood pressure drops so that systemic circulation cannot be maintained (hypovolemic shock) and tissue osmolarity can interfere with cellular function

  • hypotonic hydration - massive intake of water or damage to kidney function, low ISF electrolyte concentration (hyponatremia) which is disruptive to nervous system

• pH

  • pH sensitive cells in PCT and cCD can excrete protons/proton equivalents or bicarbonate

  • type A tubular cells recover filtered bicarbonate un urine; protons transported to urine, bicarbonate transported by sodium secondary active transport to blood

    • type B cells do the opposite to secrete additional bicarbonate

  • additional H⁺ is secreted and buffered by phosphate in urine or transported as ammonium H⁺ equivalents

• PTH increases DCT reabsorption of Ca²⁺ bringing it from urine into bloodstream, also increases phosphate reabsorption to counterbalance ionic charge

Chapter 26: Reproductive System

Gametes - haploid reproductive cells; produced by meiosis; unique due to independent assortment and homologous recombination

Gonadotropins

• GnRH - produced by hypothalamus, stimulates LH and FSH production in anterior pituitary

• FSH and LH involved in stimulation of testosterone and estrogen and spermatogenesis and oogenesis

• Testosterone and estrogen provide negative feedback to LH and FSH

  • testosterone - produced by testes in men, adrenal cortex and ovary in women; libido in women and bone mineralization, metabolic rate, RBC formation, precursor to estrogen synthesis

  • estrogen - leydig cells, sertoli cells, bone, adipose tissue in men; metabolic regulation, decreased glucose tolerance, bone resorption

• Progesterone - inhibits release of gonadotropins

• inhibin specifically inhibits FHS

Males

• spermatogenesis - formation of sperm in seminiferous tubules of testes

  • leydig cells (interstitial endocrine) - in connective tissue around seminiferous tubules, produce androgens

    • stimulated by LH to produce testosterone → negative feedback to inhibit LH and GnRH

  • sertoli cells (sustentocytes) - large columnar cells surround developing sperm, divide basal compartment and lumen, phagocytize defective sperm

    • respond to FSH stimulation to stimulate sperm proliferation and stimulate inhibin → negative feedback to inhibit FSH

  • progenitor cells (spermatogenic) - cells that develop into sperm, enveloped in sertoli cells

  • 

• mature in epididymis and released by vas deferens during ejaculation

  • ejaculate is delivery system for sperm, semen contains secretions of seminal gland and prostate; feed, activate, protect sperm

  • pre-ejaculate secretions are meant to clean and lubricate reproductive tract

• testosterone - acts on sertoli cells, induces differentiation of male accessory organs and secondary sex characteristics, stimulates protein anabolism and bone growth, sex drive

Females

• oogenesis - formation of ova in ovaries during fetal development (arrested at meiosis I)

  • mitosis - oogonium (during fetal development)

  • meiosis I - primary oocyte, at birth

  • meiosis II - completed only if sperm penetrates oocyte, each month a few dozen eggs undergo this process but only about 1 becomes mature

    • secondary oocyte is released during ovulation

    

• ovulation - follicle breaks open in ovary and releases egg into fallopian tube

  • follicle becomes corpus luteum (temporary organ to produce estrogen and progesterone)

  • oocyte in meiosis II and stays there until fertilized by sperm (completes meiosis and merges genetic material)

• ovarian cycle

  • lowered estrogen/progesterone trigger rise in LH and FSH to develop follicle and start ovarian cycle

  • developing follicle raises estrogen to induce endometrial development in uterus and positive feedback for GnRH to spike LH (FSH blocked by inhibin and estrogen); follicle fuses and ovulation of egg

  • corpus luteum produces high levels of estrogen and progesterone to maintain endometrium in a state of readiness and prevent menstruation (similar in pregnancy)

  • in absence of fertilization the CL degrades, estrogen and progesterone levels drop and FSH and LH take over, cycle restarts

• menstrual cycle

  • menstruation (days 0-4) - uterus sheds endometrium

  • proliferative phase (days 5-14) - endometrium rebuilds itself in response to rising estrogen

  • secretory phase (days 14-28) - endometrium prepares for implantation, rising levels of progesterone from CL and endometrium converts to secretory mucosa

Differences

• location/sex

• sperm produced by the billions each month, 4/progenitor cell, small with tails, only contains genetic material, does not survive fertilization (only genetic material)

• eggs produced by thousands during fetal development, only one gets through maturation process/month, one egg/progenitor cell, metabolic capability and substance of all 4 progenitor cells (polar bodies)

Human reproductive life stages

• zygote/fetal development - GnRH, gonadotropins made in high amounts for development (basic internal/external genitalia and secondary sex characteristics)

  • internal - develops from gonadal ridge and wolffian/mullerian duct tissues of early embryo (6-8 weeks); Y chromosome changes Wolffian duct to epididymis, vas deferens, etc. and AMH (anti-mullerian hormone) degrades mullerian ducts); in absence of Y chromosome wolffian duct degrades and mullerian duct becomes fallopian tubes and uterus (gonadal ridge becomes ovaries)

  • external - genital turbuncle differentiates into penis or clitoris with/without testosterone; urogenital fold becomes urethra and internal penis or vaginal tract; labioscrotal fold becomes externals of penis and scrotum or labia majora

  • mammalian embryos are inherently female and require hormones (testosterone, AMH, dihydrotestosterone) to become male

Sex

• Fertilization - zygote formation

• Implantation - fertilized zygote (blastocyte) implants in endometrium after ~6 days

• Gestation (pregnancy) - placenta (bridge between mother and fetus, has some viral/cancer properties) develops after implantation, produces large amounts of estrogen and progesterone and relaxin (supresses contractions) to maintain endometrial lining and prevent further menstruation

• Parturition (labor and delivery) - falling levels of placental hormones (drop in relaxin) trigger labor and contractions, triggers positive feedback mechanism with oxytocin until delivery

• Lactation - prolactin stimulates breastmilk production and oxytocin triggered by palpation of breast releases milk, provides nutrients and microbiota and antibodies