Lecture 30: Adipose Tissue

Adiponectin's metabolic effects on blood vessels

***Reduces all the inflammatory factors that promote athlerosclerosis and prevent endothelial dysfunction! - inhibits monocyte adhesion (first step for athlersclerosis --> prevents that!) - inhibits macrophage transformation --> foam cells (so you have decreased phagocytic activity) - decreases proliferation of vascular smooth muscle cells (VSMCs) in response to growth factors (prevents athlersclerosis!) - increases NO production in endothelial cells and angiogenesis (vasodilation!) - Decreases TNF-a production (TNF causes inflammation --> trying to prevent athlerosclerosis!)

What are the effects of leptin on fat metabolism?

- Decreases fat storage - Decreases TG content and increasing FA oxidation - Decreases in activity and expression of esterification and lipogenic enzymes - Decrease in lipogenic activity of insulin, favoring lipolysis - Increase in sympathetic-medicated energy expenditure - Increase in expression of uncoupling proteins (induces thermogenesis)

Adiponectin

- Abundant in human plasma - expressed in differentiated adipocytes Two types of adiponectin receptors: - AdipoR1 (muscle) - AdipoR2 (liver) - Binds to collagen types 1, 3, 4 in injured vessels --> important for vascular repair

Hormones produced by adipose tissue

- Adipose tissue is an endocrine organ that secretes a wide variety of bioactive peptides --> adipokines (act at local and system level!) - Affect energy homeostasis, insulin sensitivity, and nutrient-sensing pathways

Factors that decrease leptin

- B3 adrenergic activity (increases lipolysis) - androgens - Free FA (this means you have decreased TAG/lipid storage) - GH (increases glucagon --> lipolysis) - PPAR-y ligands --> increases lipid uptake/adipocytic activity???

Neural signals to adipose tissue

- Catecholamines/adrenergic (NE/epinephrine) --> epinephrine increase glucagon --> increases lipolysis and inhibit adipose tissue hyperplasia from preadipocytes - Subcutaneous adipose tissue and visceral tissue has different rates of lipid synthesis and lipolysis

Brown Adipose tissue

- Contains cells with multiple lipid droplets between lots of mitochondria -Also has UCP factor (thermogenin) - Elevated metabolic activity, rich vascularization, and a high number of mitochondria --> non-shivering thermogenesis (important during neonatal stage!) - Brown fat is stored in chest and neck in adults --> becomes active with cold temps via adrenergic stimulation (temperature control!)

Leptin main functions

- Crosses BBB, so it acts through different brain circuits (mostly hypothalamus) --> affect appetite, energy expenditure and neuroendocrine function - Produced by white adipose tissue, leptin also directly acts on peripheral tissues (muscle/pancreatic B cells) - Primary role: metabolic signal of energy sufficiency - Caloric restriction and weight loss --> decreased leptin --> physiological responses to starvation increased appetite and reduced energy expenditure - Increase in nutrient intake --> increase leptin levels --> activates melanocortin receptors --> decrease in insulin secretion (this is why leptin can contribute to type 2 diabetes!) --> decreased fat storage

Neuroendocrine function of leptin

- Decreases hypercortisolemia, inhibits stress-induced secretion of CRH, and inhibits cortisol secretion - Stimulates TRH expression and secretion --> increases thyroid hormone levels in hypothyroid patients - Levels correlate directly with the mass of white adipose tissue - Increases gonadotropin secretion and accelerates puberty (leptin has direct effects on ovary, testis, prostate, and placenta) **Leptin decreases the amount of insulin secreted because it is focused on decreasing fat storage when it is increased!

PPAR-y

- Differentiating adipocyte turns into white fat cell via PPAR - Over expression of PPAR-y into fibroblasts --> enought to confer adipocytic phenotype - Endogenous ligands for PPAR-y: prostaglandin PGJ2 and long chain FAs - After activation, PPAR-y increases expression of genes for glucose uptake, lipid uptake and lipid synthesis pathways --> so it activates adipogenesis

Estrogens

- Estrogen and testosterone are responsible for the body fat distribution (gluteal-femoral in women and abdominal in men) - Lipoprotein lipase (LPL, lipid storage) is increased in gluteal femoral region compared to men - Postmenopausal women get treated with estadiol --> increases adipocyte precuros proliferation and regulated lipid storage in region-specific manner --> increases LPL in gluteal femoral region

IGF-1/GH

- GH is a lipolytic hormone via cAMP pathways (GH increase glucagon to break down adipose tissue) - GH increases IGF-1 production in adipose tissue --> activates preadipocyte proliferation and adipocyte maturation - Deficiency in GH = central obesity - Replacement of GH = reduction in visceral adipose tissue

Glucocorticoids

- High levels of ACTH and glucocorticoids (cortisol) --> obesity - Low levels of ACTH and glucocorticoids --> adrenalectomy - Enzyme 11HSD-1 in adipose tissue converts inactive cortisone --> active cortisol - This is why the larger the adipocyte cell, the larger the activity of 11HSD-1 in converting cortisone into cortisol - Adipocyte hypertrophy generates signals like cortisol --> recruit new adipocytes **Cortisol increases adipogenesis in the face and neck

Pathophysiology of obesity

- In obesity, adipocytes will undergo hypertrophy --> insulin resistance - Free flux of FA out of adipose tissue (adipocyte hypertrophy) - Growth of adipose tissue --> decreased capillary density and increase adipose tissue vasoconstriction --> decreased BF to tissues --> tissue hypoxia --> induces inflammation --> increases cytokine concentrations (TNF increases) --> insulin resistance occurs then! (TNF is central to insulin resistance...)

Adiponectin main function

- Increase phosphorylation of insulin receptor, activate PKA (increased lipolysis), modulate NFkB pathway --> tries to decrease diabetes (increasing insulin sensitivity, increasing glucose use) --> tries to decrease inflammation (decreases macrophages, decreases TNF) ---> tries to decrease athlersclerosis (increases NO, increases angiogenesis, decreases VSMCs)

Adiponectin concentration and BMI

- Increased BMI/weight = decreased adiponectin (opposite to leptin!) --> this is why, when you lose weight, adiponectin prevents athlersclerosis - Decreased adiponectin = increased insulin resistance and obesity **SO adiponectin is important for decreasing athlersclerosis

Main biological function of leptin

- Leptin maintains the minimum level of energy during periods of caloric restriction - Low leptin levels trigger strong responses to protect the organisms from starvation while high levels of leptin (in obesity) have weak biological responses due to "leptin resistance" - Leptin activates PKA in muscle and liver (PKA imp for lipolysis) --> ATP catabolic pathways are activated --> leads to glucose transport, B-oxidation, glycolysis, mitochdrial biogenesis - HYPERLEPTIN is associated with obesity, atherosclerosis, HTN, and metabolic syndrome

Extracellular factors that regulate adipogensis (inhibitors!)

- TNF: released during obesity indicating high levels of inflammation - Resistan: promotes insulin resistance - Norepinephrine

Examples of nuclear hormone receptors expressed in adipose tissue

- Thyroid hormone receptor - androgen receptor - estrogen receptor - progesterone receptor - Glucocorticoid (cortisol)

What is adipose tissue?

- Type of connective tissue in which fat cells or adipocytes are - Should be no more than 15-30% of body weight - It is a key regulator of body's overall energy metabolism --> releases hormones and substances that target organs - An endocrine organ that contributes to internal homeostasis

Metabolic syndrome

- Upper body/abdominal obesity is associated with a cluster of metabolic risk factors for coronary heart disease - Features: insulin resistance with associated hyperinsulinemia, impaired glucose tolerance, impaired insulin-mediated glucose disposal, and type-2 diabetes mellitus; dyslipidemia, characterized by hypertriglyceridemia and low serum high density lipoproteins (HDL) levels; and hypertension. - NOTE: Other metabolic risk factors, including increased serum levels of apolipoprotein B; small, dense low-density lipoprotein (LDL) particles; and plasminogen activator inhibitor 1 (PAI1, encoded by SERPINE1) with impaired fibrinolysis have also been associated with abdominal obesity **Relisten to this part and redraw the figure/flow chart

Obesity

- disease of caloric imbalance that results from excess intake of calories above consumption by the body - BMI > 25 = overweight; BMI > 30 = obese - Central/visceral obesity = associated with higher risk of CV diseases

White adipose tissue

- more common - cells contain one large droplet of white-yellow fat in their cytoplasm - Main function: long-term energy storage/balance of the body - within the tissue, fibroblasts, macrophages, and other cells make up about half the total number of cells

Regulation of Adipogenesis

Adipocytes store triglycerides in cytoplasmic droplets covered in a coat of phospholipids and proteins --> this coat sequesters the lipids from the cytosol and regulates access of lipases to the droplet surface - Perilipin is a protein --> phosphorylated by PKA and PKG --> initiates lipolysis

Adiponectin's metabolic effects on skeletal muscle

Adiponectin: - stimulates glucose use - increases fatty acid oxidation (B-oxidation)

Examples of catecholamine receptors expressed in adipose tissue

B3 receptors

Asymmetrical biological response

Energy restriction --> decreased fat mass --> decreased leptin: Increases energy for: - Maintenance of soma - Adrenalcortical axis ***diverts energy to important brain energy rather than "unnecessary functions" Decreases energy available for: - Reproduction - Growth - Energy metabolism ***NOTE: lack of leptin leads to more extreme responses than an increase in leptin --> then you'll have an increase in leptin resistance

Adiponectin's metabolic effects on the liver

In the liver: - enhances insulin sensitivity - decreases influx of non-esterified fatty acids (NEFAs) - increases fatty acid oxidation, - reduces hepatic glucose output.

Inhibition of adipocyte lipolysis

Insulin binds to a2 receptors --> stimulates PDE3/5 --> inhibit cAMP --> decreases phosphorylated P-perilipin --> decreases lipolysis --> Insulin actually increases lipogenesis instead!

Examples of traditional endocrine hormones expressed in adipose tissue

Insulin receptor, glucagon receptor, GH receptor, TSH receptor

Factors that increase leptin (things that cause/associated with increased fat storage)

Insulin, glucocorticoids, TNFa, estrogen

Examples of cytokine receptors expressed in adipose tissue

Leptin

ANP/BNP increase lipolysis

Natriuretic peptides (ANP/BNP) --> Guanylate Cyclase (GC) receptors --> cGMP --> PKG --> phosphorylates perilipin and HSL --> stimulates lipolysis (but is not influenced or suppressed by insulin!) - Cold, cardiac wall strain, inflammation, and hypoxia all increase ANP/BNP

Regulation of lipolysis

Norepinephrine binds to B-receptor --> Activates Adenocyclase (AC) --> increase cAMP - cAMP --> Increase pKA --> phosphorylates HSL and perilipin --> lipolysis occurs

Mesenchymal cells

Pericytes (outside capillaries) --> Adipocyte precursors / mesenchymal cells --> preadipocytes/stromal cells (exhibit different properties if they're either subcutaneous or visceral!) --> brown or white adipocytes

Extracellular factors that regulate adipogensis (Activators!)

insulin, cortisol, thyroid hormone, PPAR-y ligands (Even though cortisol inhibits insulin, it depends where it is. If cortisol is in your face or neck, then it activates adipogenesis --> everywhere else, it inhibits it!!!) - Insulin --> makes sense because you're uptaking glucose, FA, etc. - Thyroid hormone***WHY??