Back to the brain again!

I feel like this whole metabolic syndrome thing is going around in circles sometimes! This paper touches on some of the key points that Lustig makes in his speech's, the paper is very information dense so I have highlighted the important points below.

• WAT dysfunction is characterized by the inability of WAT to store lipids or restrain lipolysis in the fed state, and results in elevated circulating FFAs
• insulin and leptin are the main endocrine adiposity signals in mammals
• The hypothalamus orchestrates nutrient partitioning and appetite depending on the signals it gets from leptin and insulin
• diabetic patients started on insulin tend to gain weight
• leptin administration reduces adiposity in leptin deficient rodents and humans
• Whole body insulin receptor knockout produces a significantly lower level of fat mass than adipocyte insulin receptor knockout only
• brain insulin signaling plays a pivotal role in preserving fat mass and retaining FFAs in WAT
• effects of leptin are mediated primarily via signaling in the brain
• Re-constitution of neuronal leptin receptors completely reverses the lipotoxic, dysmetabolic phenotype of leptin receptor deficient db/db mice. Conversely, deletion of the peripheral leptin receptor in mice but not the brain results in no obvious dysmetabolic phenotype or alterations in adiposity indicating that brain leptin signalling is the only important thing when considering fat mass

Brain regulation of WAT mass by leptin and insulin

• reducing neuronal leptin receptor levels by 50% in mice results in increased fat mass, while food intake seems not to be affected [56]. ( so much for calories in calories out )
• leptin stimulates lipolysis by increasing sympathetic nervous system outflow to WAT
• chronic intracerebroventricular insulin infusion can increase fat mass in mice without affecting food intake
• insulin infusion into the mediobasal hypothalamus acutely restrains lipolysis in rats, as assessed by WAT triglyceride hydrolase activity and HSL activation state, by reducing sympathetic nervous system outflow to WAT

Lipolytic flux from WAT drives hepatic gluconeogenesis

• FFA levels closely correlate with hepatic glucose production, independent of systemic insulin or glucose levels
• combined knock-out of leptin receptors in Agrp and Pomc neurons has an additive effect resulting in an approximately 30% increase in adiposity despite equal food intake
• brain leptin signaling in both Pomc and Agrp neurons plays an important role in the regulation of adiposity
• only Agrp insulin receptor knock-out mice, but not Pomc, fail to suppress hepatic glucose production during hyperinsulinemia ( hmm interesting! )