Cgref1 is a CREB-H-regulated hepatokine that promotes hepatic <i>de novo</i> lipogenesis by mediating epididymal fat insulin resistance

<b>Rationale:</b> Type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD) are interrelated metabolic disorders that pose significant health concerns. Hepatokines and other regulatory factors implicated in these diseases are incompletely understood. Here, we report on a new hepatokine named cell growth regulator with EF-hand domain 1 (Cgref1) that modulates lipid metabolism to aggravate these conditions. <b>Methods:</b> <i>Cgref1</i> was identified by microarray analysis of downregulated genes in liver of <i>Creb3l3</i> ^-/- mice. <i>Cgref1</i> ^-/- mice were subjected to transcriptomic, metabolomic and lipidomic analyses as well as metabolic assays. Gain-of-function and loss-of-function assays were performed in primary hepatocytes and cultured human and mouse cells. <b>Results:</b> Cgref1 expression is induced by hepatic transcription factor CREB-H. Secreted Cgref1 primarily targets epididymal white adipose tissue (eWAT), where insulin signalling and glucose uptake are suppressed. <i>Cgref1^-/-</i> mice showed lower tendencies of developing obesity, hyperglycaemia and dyslipidaemia, associated with compromised hepatic <i>de novo</i> lipogenesis. Thus, Cgref1 poses an advantage to maintain the normal functioning of vital organs by preserving glucose from being absorbed into eWAT. However, in circumstances where Cgref1 expression becomes excessive, eWAT develops insulin resistance, which in turn promotes hepatic glucose production, lipogenesis and MASLD development. <b>Conclusion:</b> As a hepatokine that affects blood glucose levels and lipogenesis, Cgref1 is a potential target in the intervention of metabolic disorders.