The regulation of insulin signaling and Akt/PKB activity by obesity

Abstract

Insulin is a key regulator of Akt/Protein Kinase B (PKB), which is a requisite intermediate linking the hormone to postprandial glucose uptake and anabolic metabolism. Increased adiposity, a characteristic feature of obesity, promotes insulin resistance and is linked to the pathogenesis of multiple metabolic diseases. The link between obesity and insulin resistance remains unknown, but is likely to be driven by factors secreted from adipose tissue. Specifically, researchers have identified roles for the adipocyte-derived cytokine tumor necrosis factor-alpha (TNFα) and the sphingolipid ceramide as mediators of insulin resistance that are associated with increased adiposity. However, the molecular mechanisms whereby these factors inhibit insulin signaling are not completely understood. In this two-part study on the regulation of insulin action and Akt/PKB activity by obesity, we first investigated the control of Akt/PKB activity in yellow-bellied marmots as they progressively became obese and insulin resistant prior to hibernation. Under fasting conditions, we discovered a seasonal and tissue-specific activation of Akt/PKB and glycogen synthase (GS), suggesting the existence of a novel insulin-independent mechanism regulating Akt/PKB activity during periods of marked anabolism. Secondly, we identified Mixed Lineage Kinase 3 (MLK3) as a novel intermediate in TNFα and ceramide signaling in cultured fat cells. We show that inhibition of MLK3 completely prevents signaling events stimulated by TNFα, and ceramide stimulation of c-Jun N-terminal Kinase, an important regulator of insulin sensitivity. The first study provides evidence for a novel evolutionary strategy that hibernators use to regulate anabolic metabolism through insulin resistance. Therefore, identifying the mechanism for non-insulin stimulated Akt/PKB and GS activation in these animals could lead to new treatments for metabolic diseases caused by insulin resistance in humans. Secondly, the identification of MLK3 as a required intermediate in TNFα and ceramide signaling identifies a novel therapeutic target for the treatment of insulin resistance.