Adipokines Flashcards
what is obesity
abnormal or excessive fat accumulation that presents a risk to health.
describe the histology of adipose tissue
Connective tissue
Several cell types:
Adipocytes (white/brown/beige)
Stromal vascular cells
(pre-adipocytes, fibroblasts, endothelial
cells and monocytes/macrophages)
what are the traditional roles of adipose tissue
Store energy
Cushion organs
Insulation
what are adipokines
adipokines are immunomodulatory cytokines secreted by adipose tissue that include acute phase reactants, growth factors and other inflammatory mediators, adipose tissue hormones such as leptin; and have an autocrine, paracrine, and endocrine mechanism of action.
how many adipokine proteins are there
347 protein components
what are the major adipokine classes
Metabolic adipokines
Pro-inflammatory adipokines
ECM components
Mitogenic/angiogenic adipokines
what cell factors do metabolic adipokines come from
leptin : white adipose tissue (WAT)
what cell factors do pro-inflammatory adipokines come from
visfatin : macrophages
what cell factors do ECM components come from
fibronectin : fibroblasts
what cell factors do mitogenic/angiogenic adipokines come from
Adiponectin: WAT
name some metabolic adipokines
Adiponectin
Leptin
Visfatin (PBEF, NAMPT)
name a pro-inflammatory adipokine and does it provide a mechanism for the pro-inflammatory phenotype of obesity
Visfatin
it provides a pro-inflammatory phenotype for obesity but the adaptive response morphs into a maladaptive one over time.
name some Extracellular matrix (ECM) components
Fibronectin
what does long-term obesity have on the extracellular matrix?
in long-term obesity, the extracellular matrix builds up around adipokines and thickens (fibrosis) causing the adipokine to shrink
name some Mitogenic/angiogenic adipokines
Adiponectin
name the three key adipokines
leptin
adipokines
visfatin
describe the genetic characteristics of leptin
16.7 kDa hormone
product of ob gene
where is leptin secreted
mainly from white adipose tissue (subcutaneous fat (beneath skin) > visceral fat (surrounds organs)
Also secreted by BAT, placenta, muscle, stomach etc…
what molecule has a satisfactory role
leptin (by giving fullness feeling)
what molecule is found in excess in obesity and type 2
leptin
what is leptins physiological role in as a satiety factor
Inhibits hunger by:
- counteracting the effects of (neuropeptide Y) NPY and anandamide (responsible for hunger)
promoting the synthesis of α-MSH (inhibits appetite
what is the effect of prolonged leptin release?
Over time, leptin resistance becomes a factor (individuals w/ obesity)
what is leptin’s physiological role in reproduction
- Required for fertility
-Levels can affect egg quality and in vitro fertilisation success
-Stimulates GnRH released by the hypothalamus to release FSH AND LH
what is leptin’s physiological role in NUTRIENT METABOLISM
-Enhances lipid oxidation in muscle
-Inhibits glucose-induced insulin secretion
describe the general characteristics of adiponectin
- 30kDa peptide hormone, multiple forms and segments
- Implicated in glucose and lipid homeostasis
- has anti-inflammation and anti-atherogenesis effects
-Levels drop with increased adiposity
- May be increased in older adults (>70), especially centenarians
- circulates as a multimer
is adiponectin levels increased or decreased in obesity?
decreased
true or false adiponectin counteracts leptin
true
why does adiponectin circulate in different forms
circulates in different forms in different diseased states
what forms can adiponectin be found in
what bonds hold tetramers of adiponectin together
di-sulphate bridges
how many adiponectin receptors are there
3 receptors
what are the three adiponectin receptors and where they are expressed?
AdR1 – ubiquitously expressed, most abundant in skeletal muscle, globular
AdR2 – liver, full length
T-cadherin – in myoblasts, not liver.
what part of adiponectin activates AdR1
globular area
what part of adiponectin activates AdR2
any part of the molecule activates it
what is adiponectin physiology?
Suppresses TNF-α and IL-6
Suppresses hepatic gluconeogenesis
Stimulates FFA (fatty acid) oxidation
Stimulates glucose uptake in muscle
Stimulates insulin secretion
Anti-cancerous (opposes leptin)
Who is adiponectin beneficial too and why
Mostly beneficial effects – mostly lost in obesity (as levels drop)
Possibly due to changes in adipocyte size and deposition
what are the possible therapeutic uses of adiponectin
- anti-hyperglycemic
- anti- anthropogenic
- anti- inflammatory
- could have important implications when developing new therapies for preventing/ treating obesity and obesity-related diseases
where is visfatin secreted from
exclusively visceral tissue
what is visfatin also known as
Also known as pre-B-cell colony-enhancing factor 1 (PBEF1) and Nicotinamide phosphoribosyltransferase (eNAMPT) -> produces nicotine mononucleotide
what is visfatins known roles
+ Known to be nicotinamide mononucleotide (NMN) biosynthesisER (NAD precursor)
+involved in oxidative phosphorylation
+aging and cancer
+ acts as an enzyme extracellularly to produce NMN which converts to NAD
What is the importance of visfatin secreted by macrophages?
- Visfatin is secreted by neutrophils & macrophages in response to inflammatory stimuli
- Obesity and metabolic syndrome are multifactorial diseases which includes chronic inflammation.
- Visfatin is implicated, perhaps at early stages of the development of obesity and metabolic syndrome, to reduce inflammation.
- Intracellular NAD+ concentrations correlate with visfatin protein expression upon PPARγ ligand activation
what is the link between Visfatin and NAD+ in disease
NAD+ boosting was also efficient to improve glucose homeostasis in obese, prediabetic, and T2DM animals
explain the Adipokine theory of obesity
development of metabolic disorders such as obesity and insulin resistance is a result of adipokines circulating and reduced levels or adiponectin
explain the storage Storage deficit theory obesity
there is max safe level of lipids that can be stored in adipokines before lipids get stored elsewhere ex, pancreas and kidney
explain the insulin secretion pathology of leptin
leptin decreases GLUCOSE STIMULATED INSULIN SECRETION (GSIS) (U SHAPED) so can act as a pro-diabetic
Explain leptins cardiovascular pathological effects
Role in endothelial dysfunction as it causes endothelial cells to become more inflammatory adding more adhesion molecules to drive atherosclerosis(
-> arteries become narrowed and hardened due to fat build up)
explain the pathology of leptins in cancer
In vitro – increased proliferation (breast, colorectal, prostate, ovarian and lung) and decreased apoptosis (colorectal and prostate),
Can adipokines drive cancer? How would you test this?
There is evidence to suggest that adipokines can promote cancer cell growth and metastasis. However, more research is needed to understand the exact mechanisms by which adipokines contribute to cancer progression.
In vitro experiments involve growing cancer cells in a laboratory setting and exposing them to different concentrations of adipokines to observe their effects on cell growth and proliferation. In vivo, experiments involve administering adipokines to animal models with cancer and observing the effects on tumour growth and metastasis.
experiments are not definitive of adipokine involvement in cancer
visfatin’s association w/ disease
*Extracellular visfatin can exert various deleterious effects on vascular cells, including inflammation and proliferation.
*The vasculature of visceral fat, is unique in that it drains into the hepatic portal vein (secretions of visceral fat is drained into liver).
* Plasma PBEF/visfatin can be increased in response to a sustained (90-240 minute) blood glucose elevation.
* Clinical studies are mixed, however, but suggest an association between increased circulating PBEF/visfatin with diabetes mellitus.
* visfatin activates insulin receptors and increases secretion however elevated visfatin for a long period of time can have opposing effect
what are the various adiponectin levels effects if therapeutic?
*Lifestyle correction can increase adiponectin levels (<1 week)
*Anti-diabetic therapy increases adiponectin levels
*Cannot be oral because its a peptide – stomach
*Administration w/ injections - reduces visceral adiposity, adipocyte size and body weight (mice)
But… does not lower blood glucose in diabetic animals
