Effects of Cortisol:1) Stimulates gluconeogenesis (from AAs) in liver2) Stimulates glycogen synthesis in liver (long term effects)a.3) Stimulates protein catabolism, especially in muscle 4) Inhibits protein synthesis in most cellsa. Breaks down prt primarily in SM, aa’s release are targeted towards the liver. Cortisol will aslo inhibit aa uptake in other cells besides the liver.5) But, increases protein synthesis in liver6) Stimulates lipolysis in adipose tissue (liberates free FAs for energy metabolism or can be converted into glucose)7) Directly opposes the action of insulinGenerally hyperglycemic, lipolytic, ketogenicIndirect effects via glucagon, GH, epi - Especially lipolytic actions of GH and epiCortisol  Defends against hypoglycemia Builds up long-term stores of glycogen so that catecholamines can cause short-term release. (Epi from adrenal medulla, and norepi from sympathetic nerves) Mobilizes energy from stores during fasting/starvationOther Cortisol Actions- Anti-inflammatoryo synthesis of arachidonic acido synthesis of eicosanoid paracrines - Immunosuppressiono cytokine releaseo Ab productiono leukocyte activity- Ca2+ loss from bodyo Bone demineralization (osteoporosis  evolutionary trade-off)o renal Ca2+ excretiono intestinal Ca2+ absorption- Effects on brain o Mood changeso Memory and learning o Enhances memory of traumatic eventsCortisol PathologiesHypercortisolism (= Cushing’s Syndrome) 1) Primary (pversecreting in Adrenal gland)o Oversecreting adrenal tumor, not under control of ACTH 2) Secondary (resides in Ant. Pituitary)o Oversecreting pituitary tumor (ACTH), no negative feedbacko control = Cushing’s Disease 3) Iatrogenico Physician-caused, due to glucocorticoid therapyHypocortisolism 1) Primarya. Undersecretion of all adrenal steroids, often due to autoimmune attack (= Addison’s Disease). Also inherited defects in specific synthetic enzymes, cause various symptoms.2) Secondarya. Impairment of anterior pituitary or hypothalamus3) Acutea. Abrupt withdrawal of therapeutic glucocorticoids4) Ectopic ACTH syndrome. Small cell carcinoma of lung involves ACTH- and ADH-secreting neuroendocrine cells- Thyroglobulin molecules are rich in tyrosine rich- Iodine comes from blood, diffuses out to EC, pumped in through Na dependent I symporter. Iodide builds up in cell. o Comes out through apical membrane through Pendrin (Iodide-Cl exchanger)o Iodide is very reactive, spontaneously reacts with tyrosine to form: Iodine atoms attach to Tyrosine When both of C are iodinated, becomes diiodotyrosine.  Monoiodotyrosine when one escapes.o T4= weak thyroid activity, mainly a precursor for T3o T3 comes from random chance of 1 double iodinated and one single iodinated thyroglobulin.- Free T3/T4 would immediately diffuse out, cannot be stored in aqueous membrane. Stored as part of structure or protein to not diffuse.- When TSH signals to thyroid cell to endocytose cell, degridative enzymes break down thyroglobulin, T3 and T4 are released from protein backbone (90% T4, 9% is T3, 1% is rT3)  diffuse out of cell (via MCT), enter plasma and bind to specific (Thyroid Binding Globulin renders the hormone capable of being soluble) or non-specific proteins (albumin (most abundant)). o Lipophylic hormones: steroid hormones and thyroid hormones.- T3 +Thyroid hormone receptor stimulates metabolism (slow to develop, long lasting, widespread)o T4: prohormone, ring on right next to r group in inter-ring, other is called outer-ringo T3: 3 Iodines, singly iodinated outer-ring.o rT3: inner-ring is singly iodinated. Inactive isomer.- Target cell can adjust production of final active hormone according to its needs at the time.- Deiodinase (D): membrane bound enzymes in target cells that takes I off T4.o D1&3 inside plasma membrane D3 inactivates thyroid hormones in target cells. (T4 rT3, T3 T2) D1 can deiodonate both rings, outer-ring  T3, inner-ring rT3?o D2: outside of smooth ER membrane. Turns on T3 production, makes cell more responsive to thyroid hormone. Activator of prohormone. Regulated enzyme by ubiqutination (attaching ubiquinone), targets enzyme for destruction in the proteasome. D2 can also remove iodine from outer-ring of rT3 or create T2 (also inactive).o  These enzymes Thyroid Hormone Effects:1) Stimulate:a. Na/K ATPaseb. oxidative phosphorylation c. protein synthesisd. lipolysis2) Increased O2 consumption and heat production (because of metabolic activity)3) Increased respiration, heart rate, stroke volume, & cardiac output4) Stimulate appetite5) Required for bone, brain, in utero development.a. Mother thyroid hormone stimulates fetus growth for first 10 weeks. Maternal TH does not cross palcenta well, so requires fetus to make its own hormone.^Necessary for body growth, cannot grow without thyroid hormones.o Thyrotropin Releasing Hormone (TRH)  Ant Pit (TSH) circulates and stims thyroid follicle cell. Iodide necessary in thyroid gland for feedbacko Primary Hypothyroidism lethargic, cold, sleepy (children= permanent retardation of phys/mental growth). High TSH with no suppression, so thyroid gland grows to large proportions (goiter)o Most common thyroid disease: Hashimotos Disease: cytotoxic T cells attack thyroid follicle cells, so have symptoms of hypothyroidism. Lack of native feedback so TSH stims growth ofthyroid gland.o Treat with thyroid hormone supplementation.o Graves disease: hyperthyroid condition (autoimmune), circulating autoantibodies that mimic TSH, stimulates TSH receptor, which activates thyroid follicle and pumps out a lot of thyroid hormone.o Causes: excessive heat production, sweat, lose weight with high metabolism, but eat a lot (might gain weight), irritable, CARDIOVASCULAR heart beats too fast.Exophthalmos: fat in back of eye grows too much and pushes eyes forward,o Goiter in Graves Disease: Not easily treated  Gamma