IRS4belongs to the insulin receptor substrate family, acting as a scaffold for tyrosine kinase–mediated signaling, integrating signals downstream of receptors such as insulin, IGF-1, and leptin. Its expression has been detected in human hypothalamic nuclei (including the paraventricular nucleus) and the pituitary gland, aligning with a plausible neuroendocrine role.
The precise mechanisms by which IRS4loss leads to reduced TSH secretion are not fully defined. Disruption of leptin signaling—a pathway known to modulate TRH and TSH secretion—has been proposed as one link between IRS4deficiency and central hypothyroidism. In contrast to humans, Irs4 knockout mice do not develop central hypothyroidism under normal or induced hypothyroid conditions, suggesting species differences, functional redundancy among IRS proteins, or compensatory mechanisms in rodents.
IRS4