Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production
The mice in this study were full knockouts for the Ins2 gene and also had either no knockout or half knockout of the Ins1 gene. Reduced insulin gene dose reduces insulin secretion which completely protected them from the obesogenic effect of the Surwit (D12330) diet. You cannot become hyperinsulinaemic in response to Surwit's maltodextrin/sucrose if you have only one out of 4 insulin genes functioning (with two out of four you can). Lack of hyperinsulinaemia normalises fat storage as one effect. Lack of hyperinsulinaemia also eliminates long term insulin-induced insulin resistance as a second, non related effect. Both effects are independently the direct result of reduced insulin exposure. The mice stay slim because they are eu-insulinaemic on a Surwit diet. The mice stay insulin sensitive because they are eu-insulinaemic on a Surwit diet. One cause, two responses. Shared causality tends to give correlated effects. But we all know about correleations and causality...
Despite being insulin sensitive the low Ins2 mice do not become obese because their knockouts stop them making enough insulin to achieve this. They are insulin sensitive but they are genetically unable use their insulin sensitivity. They are beautiful, to me at least. In an abstract sense.
Okay, have some graphs:
Top line in pink, obesogenic diet with normalish insulin phenotype, they get fat. Red line is the obesogenic diet with blunted insulin secretion. They don't get fat.
And insulin resistance: just consider the 52 week values here, these mice are a bit hit and miss re glucose/insulin function very early in life. By a year they show their true phenotype.
Just to reiterate: On the obesogenic diet fasting insulin is high because there has been a year of exposure to high insulin from the maltodextrin/sucrose of the Surwit diet when combined with a fairly normal pancreas, pink circles. The red triangles are the same diet but with blunted insulin exposure due to their Ins1 partial gene knockout. Ergo, low insulin exposure is causative of low insulin resistance at a year of age, even on the Surwit diet.
So. Insulin sensitivity, a surrogate for low insulin exposure, is a Good Thing. Using that insulin sensitivity by increasing insulin exposure will make you fat and insulin resistant as two separate effects from the same change.
I'll take a brief pause here for that to sink in before looking at the next paper from Jim Johnson's lab which translates these findings in to longevity studies. Which are really weird.