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R1 (GDU1). Phylogenetic analysis identified two clades of LOG2/MGRN1-like proteins in vertebrates and plants. The ability of MGRN1 to functionally replace LOG2 was tested. MGRN1 ubiquitylates GDU1 in vitro and can partially substitute for LOG2 in the plant, partially restoring amino acid resistance to a GDU1-myc over-expression, log2-2 background. Altogether, these results suggest a conserved function for the N-terminal domain in evolution.

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ssess the physiological effects of MGRN1 on energy and glucose homeostasis, we generated animals doubly mutant for Mgrn1(md) and A(y), Lep(ob), or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1(md). Mgrn1(md) suppressed the obesity, hyperglycemia, and hyperinsulinemia of A(y) mice. Mgrn1(md) suppressed A(y)-induced obesity by reducing food intake, and reduced adiposity in Lep(ob)/Lep(ob) females, but did not alter the body weight or body composition of mice fed a high-fat diet. There was no effect of Mgrn1(md) on weight gain, body composition, energy intake, or energy expenditure in Mc4r-null animals. Mgrn1(md) reduced circulating insulin concentrations in DIO, A(y), and Mc4r-null but not Lep(ob)/Lep(ob) mice. The effect of Mgrn1(md) on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1(md) mice segregating for either A(y) or Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with A(y) and Mc4r mice, respectively. The effect of Mgrn1(md) on insulin sensitivity of Mc4r-null mice suggests that Mgrn1(md) may be increasing insulin sensitivity via the hypothalamic melanocortin-3 receptor pathway.