STAT3 signalling is required for leptin regulation of energy balance but not reproduction

Abstract

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…To dissociate the effects of both hormones and gain insights into the role of PI3K downstream of leptin action, we deleted PI3K catalytic subunits only in LR cells. A similar approach has produced compelling data on the requirement of STAT3, STAT5, and PTEN actions downstream of leptin signaling (14,23,26). Because the coexpression of LR and InsR has not been systematically investigated, we assessed if lack of insulin signaling in LR cells accounts for the phenotype observed following LR PI3K deletion.…”

“…Selective mutations in LR tyrosine residues have produced compelling data on the effects of specific signaling pathways in leptin function (23)(24)(25). Mice with blockade of LR-activated STAT3 signaling are obese and have disrupted thyroid and adrenal axes.…”

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

“…db/db mice are known to develop obesity due to hyperphagia that is sustained by the defective leptin circuitry (Bates et al 2003) and compensate for the obesity-associated insulin resistance by pancreatic beta-cell hyperplasia, thereby maintaining only mildly elevated blood glucose levels (Davis et al 2010). Under subordination stress, db/db mice became even more hyperphagic thus likely contributing to persistent increase in plasma glycaemia.…”

Decelerated vascularization in tissue-engineered constructs in association with diabetes mellitus in vivo

“…The experiments were conducted in accordance with the German legislation for the protection From the third to fourth week, obesity starts [16] and the blood glucose level begins to rise between the fourth and eighth week [17]. The mice show polyphagia, polydipsia, and polyuria as well as a compensatory hyperplasia of the pancreatic beta cells with hyperinsulinemia [17].…”

“…The mice show polyphagia, polydipsia, and polyuria as well as a compensatory hyperplasia of the pancreatic beta cells with hyperinsulinemia [17].…”