Week 17 Flashcards
UCP-1
Uncoupling protein -1, expressed by brown and beige adipocytes in their mitochondria. Serves to allow proton leakage across the mitochondrial membrane, thus generating heat at the expense of ATP
Types of adipose tissue
Visceral or subcutaneous
White, brown or beige
Beta adrenergic stimulation of adipose tissue
leads to increased lipolysis
adipocytokines secreted by adipose tissue
leptin
adipsin
adiponectin
How do Beta cells sense glucose concentrations?
They express cell surface GLUT2, which imports glucose from circulation and glucokinase, which phosphorylates it so that it cannot re-exit the cell (leading to glucose 6-phosphate)
Increased glycolytic flux within the B cell leads to glycolysis and ATP/ADP ratio increase that is sensed by the cell and leads to depolarization and release of insulin.
What are some metabolic assays for monitoring insulin sensitivity in muscles?
muscle uptake of radio-labelled glucose
-AKT phosphorylation in response to insulin
Tools to assess glucose metabolism
- Glucose Tolerance Test (feed glucose and track clearance, can also track insulin secretion)
- Insulin tolerance test (injection of insulin)
Clamps
Hyperglycemic clamp technique
The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The hyperglycemic clamps are often used to assess insulin secretion capacity.
Hyperinsulinemic-euglycemic clamp technique
The plasma insulin concentration is acutely raised and maintained at 100 μU/ml by a continuous infusion of insulin. Meanwhile, the plasma glucose concentration is held constant at basal levels by a variable glucose infusion. When the steady-state is achieved, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue insulin sensitivity. The hyperinsulinemic clamps are often used to measure insulin resistance.
Which types of diabetes can each clamp type test for?
Hyperglycemic clamp assesses insulin secretion capacity, and is thus used for T1D.
Hyperinsulinemic-euglycemic clamp measures insulin resistance and therefore is used to assess T2D.
Cachexia
a “wasting” disorder that causes extreme weight loss and muscle wasting, and can include loss of body fat.
Metabolic state of ATMs in obesity
In obesity, ATMs adopt a metabolic activation state with prominent lysosomal activity, with the main purpose to clear dead adipocytes.
Adipose tissue macrophages in obesity
ATMs expand to over 50% of cell in obese adipose tissue, due to increased proliferation and trafficking of blood monocytes
Enriched in visceral fat
ATMs have inflammatory phenotype in obesity
How was a role for TNFa discovered in adipose tissue?
Mice were put on a glycemic clamp (?) and treated with antibodies that prevented TNFa signaling. These mice were significantly more sensitive to insulin.
Experiment showing a role for macrophages in insulin resistance
Mice were created that specifically lacked JNK signaling in macrophages (downstream of TNFa and IL1B).
These mice showed similar obesity during HFD to WT mice, but showed increased insulin sensitivity when tested on hyperinsulinemic-euglycemic clamp studies
How do ATMs control thermogenesis?
alternatively-activated ATMs respond to IL-4 in BAT to promote thermogenesis
How do eosinophils control glucose metabolism?
Adipose tissue eosinophils are the main source of IL-4 in the tissue and there is a lack of alternatively-activated macrophages in the adipose in their absence. Eosinophil-deficient mice on HFD have impaired insulin sensitivity.
What are the main producers of IL-4 in adipose?
Eosinophils
How do eosinophils control thermogenesis?
Eosinophils promote the beige adipose tissue through IL-4 and ATMs, which leads to heat generation as opposed to lipid storage.
How do T cells influence adipose tissue?
In obese fat depots, CD8 T cells are increased and lead to the recruitment of macrophages from circulating monocytes. In lean fat depots, most T cells are CD4 and/or Tregs.
Depletion of CD8 T cells decreases inflammatory parameters in adipose and improves glucose control
Roles of Tregs in adipose tissue
Visceral-AT specific Tregs have been found to correlate with lean adipoe deposits. These Tregs uniquely express PPARg, accumulate with age, and are responsible for the effects of the diabetes drug pioglitazone
Tregs in aged adipose may promote insulin resistance though
pioglitazone
Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. It modulates the transcription of the genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver.
This has been shown to rely on adipose tissue resident Tregs.
What do VAT Tregs require?
VAT Tregs are highly enriched in particular TCR variable gene expression, require Foxp3 for VAT ressidency, express PPARg, and rely on IL-33 signaling for maintenance.
Mast cells in adipose tissue
Increased mast cells in obese adipose tissue. Mast cell KOs had decreased adiposity and increased glucose homeostasis
Treatment with mast cell stabilizers led to similar results as mast cell KO mice.
