Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons

Abstract

ObjectiveThe GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis.MethodsTo determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR). The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated.ResultsOur results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice.ConclusionThese findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.

Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons

“…However, LepR GHR KO mice utilized less glucose during a hyperinsulinemiceuglycemic clamp (Fig. 2H), confirming previous findings by Cady et al (21) showing insulin resistance after GHR ablation in LepR cells. We next performed an insulin tolerance test (ITT) to determine the capacity of the animals to recover from insulin-mediated hypoglycemia.…”

“…However, it is not known how GH secretion pattern affects the activity of GH-responsive neurons. Recent studies investigated the metabolic phenotype of mice deficient in GHR in LepR cells (21,22). These studies found that LepR GHR KO mice have normal food intake and body weight, but they present hepatic insulin resistance (21).…”

“…B) Glucose utilization during a hyperinsulinemic-euglycemic clamp (P = 0.4274; n = 3-4). C ) Blood glucose levels during an ITT (n = [18][19][20][21][22]. D) AUC of the ITT (P = 0.6876).…”

“…The role played by brain GH signaling to regulate metabolic responses is beginning to be revealed. GHR ablation in leptin receptor (LepR)-expressing cells leads to hepatic insulin resistance and impaired peripheral lipid metabolism (21). Another study found that GH signaling in agouti-related protein (AgRP) neurons represents a cue during food deprivation to trigger key adaptive responses to conserve limited fuel stores (22).…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…Later, quantitative PCR and immune-histochemical studies confirmed a near ubiquitous expression of GHR throughout the brain of humans as well as rats and mice (reviewed in (253,254,255)). Particularly high expression levels of GHR was observed in the choroid plexus, pituitary, hippocampus, thalamus, and hypothalamus (256). It was further observed that GH-binding in brain tissue decrease as a function of age (257) along with age related decline in GH production as well as cognition and memory (258).…”