Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation

Jingxiang Huang, O. Nelson, Heiko Jansen, Elizabeth Galbreath, Kurt Morgenstern, Jamie Gehring, Kimberly Rigano, Jae Lee, Jianhua Gong, Adam Shaywitz, Chantal Vella, Charles Robbins and Kevin Corbit

Cell Metabolism 2014. 20: 376-82.

Abstract

The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition.

Our Thoughts on This Paper

This paper uses a very atypical model system to look at the relationship between diabetes and obesity. In many cases, elevated adiposity is associated with insulin resistance and type II diabetes. However, there are both clinical and model organism cases in which elevated adiposity does not lead to insulin resistance. One of these is grizzly bears, which in the pre-hibernation state dramatically increase their body weight while maintaining insulin sensitivity.

In this study, Kevin Corbit's group at Amgen looked at insulin sensitivity and lipid homeostasis in bears that were about to hibernate, mid-hibernation and post-hibernation. Contrary to the model of adiposity -> insulin resistance they found that the pre-hibernating, "obese" bears had improved peripheral insulin sensitivity. They then identified elevated PIP3 dependent signaling potentially due to increased serine phosphorylation of PTEN as a potential mechanism underlying these effects. PTEN normally dephosphorylates PIP3 and desensitizes cells to the effects of insulin. The serine phosphorylation of PTEN causes downregulation of this phosphatase and potentially could cause insulin sensitization.

This study brought an interesting new perspective to our understanding of the relationship between diabetes and adiposity. The mechanism suggested by the authors, elevated PTEN phosphorylation causing adipose tissue insulin sensitization is interesting but brings up many more questions. Among those, what causes PTEN phosphorylation in this system, and how is this signal propagated. More technically, the underlying metabolic changes comparing hibernating animals to non-hibernating animals (increased lipolysis, decreased insulin sensitivity) may be more a result of inactivity than of adipose derived changes. In grizzlies, whether the metabolic changes are mechanistically rooted in adipose tissue, rather than signals from the brain, muscle or pancreas can not be determined from these studies, but this provides interesting an interesting context for us to think about the physiological and mechanistic differences between metabolically healthy and unhealthy obese states.

The slides used in our journal club presentation are shown below:

Written by Dave Bridges on Aug. 21, 2014.

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