Adipose Tissue and Insulin Resistance 4-3

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680 - Endo - Komar (1hr)

Summarize the process of adipogenesis and be able to define determination and differentiation

Adipocytes are derived from multipotent mesenchymal stem cells. First is determination (commitment of a pluripotent stem cell to adipocyte lineage). This results in the conversion of stem cell to a preadipocyte (cannot be distinguished from precursor cell but has lost potential to differentiate into other cell types). Next is differentiation, the preadipocyte takes on characteristics of mature adipocyte by acquiring the machinery necessary for lipid transport & synthesis, insulin sensitivity & secretion of adipocyte-specific proteins.

.. PPARy is an important gene for adipocyte differentiation.. cell lineage for adipocyte is not specific (mesenchymal cell can become osteocyte or myocyte as well)

Recall the primary physiological roles of adiponectin:
1. liver
2. muscle
3. vascular wall

1. ↑ insulin sensitivity; ↓ hepatic glucose output; ↑ FA oxidation...
2. (+) glc. use; (+) FA oxidation
3. (-) expression of adhesion molecules so (-) monocyte adhesion; (-) macrophage transform. into foam cells; ↓ VSMC proliferaton

Recall the primary physiological roles of leptin

satiety factor
-increases glucose uptake by skeletal muscle
-increases TRH expression and secretion from hypothalamus
-decreases insulin secretion & synthesis of pre-proinsulin

also has direct effects on gonads, regulation of immune function, hematopoiesis, & bone development

Recall the primary physiological roles of resistin


Recall the primary physiological roles of TNFa

- genes involved in uptake and storage of non-essential fatty acids & glucose
- insulin signaling via ↑ degradation of IRS-1&-2

= implicated in pathogenesis of obesity & insulin resistance

Recall the primary physiological roles of IL-6 in:
1. exercising skeletal muscle

1. increases glucose uptake and (-) inflammation

Recall the primary physiological roles of IL-6 in:
1. adipose and hepatic tissue

1. pro-inflammatory, and it impairs insulin-induced IR and IRS1 phosporylation, therefore inhibiting the effect of insulin

Recall the primary physiological roles of PAI-1

Serine protease inhibitor of uPA and tPA

decreases fibrinolysis thereby stabilizing fibrin the matrix for vascular smooth muscle cell (VSMC) migration & promotes VSMC proliferation

-increased conc. in obesity & insulin resistance & correlation w/future risk of type 2 DM & CVD

Recall how adipose tissue is suspected to impact cardiometabolic health focusing on FFA and inflammatory signals

Under obese conditions, adipocytes lose the capacity to efficiently store triglyceride, leading to FFA release into the circulation. FFAs and other adipocyte-derived factors converge at ATMs to trigger a cascade of local events in fat through which ATMs produce proinflammatory mediators, such as TNF-α and PAI-1. These factors can potentiate adipocyte dysfunction and insulin resistance, which sustains FFA release and stimulates feed-forward regulation of inflammatory cytokine production in fat. PAI-1 release can increase thrombotic risk, while shunting of FFA to ectopic sites such as the liver and skeletal muscle contributes to systemic insulin resistance. This combination of factors can contribute to the pathogenesis of cardiovascular disease and type 2 diabetes with obesity

Review the function of various gut hormones focusing on appetite and insulin secretion

hormones that stimulate appetite:
(+) NPY, AgRP, Ghrelin, MCH, Orexins
decrease appetite:
(-) CCK, GLP-1, POMC, Leptin, Insulin, PYY, PP, Oxm, CART

Outline the concept of metabolic syndrome

complex of interrelated risk factors for developing CVD & DM. conditions are:
hyperlipidemia (elevated TGs)
low HDL levels
central adipocity
-insulin resistance may be the cause of metabolic syndrome

describe the following for white adipose tissue:
1. role
2. where it's located

1. storage of lipids for energy, role in glucose metabolism, endocrine organ
2. adipocytes, CT matrix, nerves, immune cells, stromo-vascular cells

describe the secretion of Leptin

secreted in direct proportion to amount of adipose tissue mass
secretion is:
(+) by insulin, glucocorticoids, TNFa & estrogen
(-) by B3-adrenergic activity, androgens, FFA, GH

which splice form of the Leptin receptor is biologically active?

Lepr-b long form, has BOX2 & STAT req'd for STAT3 signaling.

describe the relationship between adiponectin and insulin resistance

inverse relationship

describe the adiponectin compound and its receptors

can be post-transcriptionally modified yielding low molec weight (3-6 monomers) & high molec weight (12-18 monomers)
-receptors are transmembrane, but distinct from GPCRs

Recall the primary physiological roles of IL-6

↓ secretion of adiponectin
↓ expression of insulin receptor signalling components
= circulating [IL-6] (+) correlated with obesity, impaired glc. tolerance & insulin resistance

Recall the primary physiological roles of Caspase-1

processes pro-forms of IL-1β and IL-18 to active their forms

These cytokines are players in causing the inflammatory state associated with obesity

describe the difference between adipose tissue macrophages (ATM) interface in lean & obese people

obese, size of adipocytes is increased & # of macrophages is increased (proinflammatory state)
-lean there adiponectin promotes B-oxidation
-also obese there is decreased adiponectin & increased FFA's, TNF, IL-6 & other inflammatory cytokines leading to ectopic lipid deposition & proinflammatory state

The adipose tissue of lean subjects contains few macrophages, and secretes relatively high levels of adiponectin, and low levels of inflammatory cytokines. β-Oxidation of lipids in muscle is high, and there is little ectopic fat in the muscle and liver. With obesity and insulin resistance, adipose tissue contains many macrophages, and the tissue secretes high levels of many adipokines, and low levels of adiponectin. This adipose tissue may be limited in its lipid storage capacity, and this feature, along with the pro-inflammatory state, promotes ectopic lipid accumulation

describe the role of FetA in promotion of insulin resistance

glycoprotein produced by the liver. binds free fatty acids which then bind to TLR4 receptor on adipocyte activating NF-kB which upregulate transcription of inflammatory genes causing production of inflammatory cytokines that leads to insulin resistance.

describe how the type & location of adipose tissue determines risk for type 2 DM & CVD

hypertrophied adipose deposited in visceral fat has the highest increase in risk for DM & CVD.

-subcutaneous fat & hyperplasia(unclear) of adipocytes does not cause an increase in risk of risk for DM & CVD

describe the types of cytokines released by:
1. visceral adipose
2. subcutaneous adipose

1. IL-6, PAI-1, Resistin, Angiotensinogen, ACE, 11BHSD1 (converts inactive cortison into active cortisol & glucocorticoids, increasing adipocyte formaiton), & Caspase-1

2. Leptin, TNFa, Adiponectin

give a general overview of the regulation of food intake/appetite

the hypothalamus orchestrates
behavioral, autonomic, and endocrine actions that control energy balance. Nonhomeostatic control of appetitive behavior and locomotor activity can also influence energy balance through corticolimbic systems that control learning, memory, reward, and choice.

Outline the theory behind impact of bariatric surgery:
1. removal of stomach
2. interposition of ileum

1. less ghrelin (which is orexigenic [stimulates appetite]) b/c it is primarily secreted from fundus of stomach.
2. early exposure of ingested food to ileum causes increased GLP-1 secretion from L cells leading to:
-slowed gastric emptying
-decreased apoptosis of pancreatic B cells
-increased growth & differentiation of B cells
increased secretion of peptide YY & amylin (amylin can synergize w/leptin & PYY to increase satiety, decreasing food intake)

what are treatment options for obesity, metabolic syndrome & typeII DM?

lifestyle changes
pharm intervention
bariatric surgery

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