What is T2D?
low grade chronic inflammatory condition characterized by insulin resistence and failure of pancreatic beta cells to compensate
What is T2D strongly linked to?
obesity
What is human obesity defined as?
BMI >= 30
What are the two types of adipose tissue and what do they do? Which type is more present in apple shaped people?
brown adipose tissue –> dissipates energy as heat
white adipose tissue –> energy storage, visceral – cushions organs (people with apple shape have more visceral fat)
What are the metabolic effects of insulin signaling?
glucose uptake and storage
- surface translocation of GLUT4
- glycogen synthesis
- limits gluconeogenesis
triglyceride storage
- enhances lipid synthesis
- reduces lipolysis
protein metabolism
- a.a. uptake
- decreased proteolysis
Describe the insulin signaling cascade briefly
insulin –> IR –> P13K –> AKT
When insulin resistance begins, what happens to beta cells in the short term vs the long term?
- short term: appropriate compensation – elevated insulin, normal glucose
- long term: failure to compensate – T2D
What happens when there is insulin resistance and inflammation in adipose tissue?
- adipocytes produce and release free fatty acids (FFAs) and insulin-resistance-provoking pro-inflammatory cytokines (IL-6, TNF, resistin).
- These factors contribute to the accumulation of toxic lipid metabolites in myocytes and hepatocytes, which impair insulin signaling and activate inflammatory pathways which impair the insulin signal transduction.
- mitochondrial dysfunction predisposing to DAG accumulation and nuclear PKC activation as well as generation of ROS and more ER stress further exacerbate insulin resistance
Describe the two main animal models of obesity and insulin resistance
- diet-induced obese (DIO) mouse: placed on HFD for weeks, mice devleop visceral adiposity, insulin resistance, glucose intolerance, and hyperglycemia
- ob/ob mouse (genetic mouse): leptin regulated food intake and enhances metabolism; leptin-deficient mice
Compared to lean individuals, what do obese individuals have?
- more circulating FAs and a.a.s
- hyperinsulinemia
- hyperglycemia
- alterations to some apidokine (e.g. more leptin)
- elevated pro-inflammatory cytokines (IL-1B, IL-6, TNFa) –> worsenes glucose tolerance
Describe how obesity-associated dysbiosis contributes to the activation of the IS?
- contributes to more gut permeability, facilitating the leakage of microbial products and oral Ags across the gut epithelium
- together with lipid excess and dying apidocytes, these serve as potential sources of Ags and co-stim molecules for the activation of VAT B and T cells, a process that can take place in draining LNs or locally in the VAT
Describe the role of macrophages in obesity-linked inflammation
- macrophages accumulate in both visceral and subcutaneous fat and are the major producers of TNFa in fat
- TNFa signaling in adipocytes causes them to become insulin resistant
- macrophage-derived IFNg and TNFa can stimualte adipocytes to secrete chemokines that help recruit T cells to the adipose tissue
Describe how two hormone’s levels change in obesity in the adipose tissue. How does each hormone contribute to inflammation (normally)?
- leptin increases – Th1 promoting
- adiponectin decreases – suppresses immune activation and promotes M2 polarization
Describe how T cells regulate VAT macropahge polarization
- obese adipose tissue in enriched for Th1 cells
- Th2 and Treg are decreased in obese adipose tissue
- Tregs and less functional in an obese environment
net result: more M1 polarization and more inflammation
Describe the role of B cells in the pathogensis of obesity-linked insulin resistance
- obese B(null) mice show improved metabolic function
- B cells can be pathogenic, but specific subsets (e.g. B1 cells) can have regulatory properties as well
Describe the inflammation in changes in the gut: compare lean vs obese individuals
lean
- anti-inflammation innate IC subtypes maintain homeostasis and generate commensal-tolerating reponses
- Tregs regulate gut homeostatis by producing the anti-inflammation cytokine IL-10
obese
- IC populations shift toward a pro-inflammatory phenotype (more gd T cells, Th1 cells, CD8+ T cells that secrete pro-inflammatory cytokines, include IL-17 and IFNg, respectively
- more inflammation –> more intestinal permeability
Describe how obesity is associated with changes to the gut microbiota and intestinal barrier function: compare lean vs obese
lean
- intestinal barrier is intact
- IEC produce tolerogenic responsees to commensal bacteria
- PRR signaling maintains homeostasis
obese
- consumption of HFD lessens diversity and imbalances bacterial sps
- mucin decreases
- bacteria penetrate gut barrier to trigger PRR signaling –> inflammation
- pro-inflmmatory cytokines can act on IECs to disrupt barrier function
Describe how gut Ags gain access to VAT
- during the development of obesity, gut microbiota is altered and microbial structures like LPS are absorbed by the gut
- food Ags and LPS are association with chylomicrons, which transport triglyercides and are cleared in adipose tissue
- Ags associated with the chylomicrons could be absorbed –> recruitment and activation of T cells in adipose tissue, contributing to inflammation
What food Ag activates Tregs?
SCFAs
What nutrients help maintain mucosal barrier integrity in the gut?
- polyunsaturated fatty acids
- saturated fatty acids
- vitamin A
- vitamin D
- indole 3-carbinol
What kind of other disease are linked to obesity-associated IS complicaitons?
- respiratory infection
- dementia
- atherscleoris
- diabetes
- arthritis
describe the autoimmune component that is observed in patients with obesity
- presence of autoAb
- oligiocolonal expansion of VAT-infiltrating T cells
- excessive inflammation that drives insulin resistance can contribute to loss of tolerance
