Loss of growth hormone–mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity

What is it about?

Growth Hormone (GH) and insulin are pleiotropic hormones that not only counteract their action during glucose and lipid metabolism but also share protein anabolic functions, and thus providing complexity to how we understand their interplay during normal physiology and metabolic disorders. Our study addresses the molecular basis for the high degree of insulin sensitivity, despite obesity, seen in long-lived mice with the loss of Growth Hormone (GH) receptor signalling (Ghr null) and in an Ecuadorian cohort with GH receptor deficiency. Enhanced insulin sensitivity is also evident in humans prior to obesity as a result of insufficient GH action. In addition, intermittent fasting and calorie restriction, interventions that dampen GH circulation promote insulin action. On the contrary, under pathological conditions of GH excess (e.g. acromegaly, pituitary tumours or high dose GH treatment) the diabetogenic actions of GH become apparent. Our study has used mouse models with engineered deletions to regions of the GH receptor responsible for the signalling process, allowing us to conclude that the transcription factor STAT5 is responsible for GH-induced insulin insensitivity, which is the consequential outcome of both gluconeogenesis (glucose release from non-carbohydrate sources) suppression and elevation of glucose metabolism in muscle and adipose tissues. We have dissected the altered regulatory steps at both the transcript and protein levels to present a schematic, which encompasses key changes responsible for the insulin sensitivity, clarifying an issue that has remained unresolved for over 50 years.

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