Compositions and methods of use for treating metabolic disorders

A complex comprising a first heterodimer and a second heterodimer, each of the first heterodimer and second heterodimer comprising:

• (i) a first polypeptide comprising from the N-terminus to the C-terminus:
• a first human IgG1 Fc comprising a first hinge region, a first CH2 domain, and a first CH3 domain comprising at least one substitution selected from the group consisting of Q347W/Y, T366W/Y, and T394W/Y, according to EU numbering, and
• (ii) a second polypeptide comprising from the N-terminus to the C-terminus:
• a second human IgG1 Fc comprising a second hinge region, a second CH2 domain, and a second CH3 domain comprising at least one substitution selected from the group consisting of T366S, L368A, T394S, F405T/V/A, and Y407T/V/A, according to EU numbering;
• wherein the first polypeptide dimerizes with the second polypeptide, wherein either the C-terminus of the first polypeptide or the C-terminus of the second polypeptide is conjugated to the N-terminus of a GDF15 mutein via a linker, wherein the GDF15 mutein comprises a contiguous amino acid sequence at least 98 amino acids long and at least 95% identical to a corresponding stretch of the amino acid sequence of SEQ ID NO:1, and wherein the GDF15 mutein comprises a D5T substitution relative to the amino acid sequence of SEQ ID NO:1;
• wherein the GDF15 mutein in the first heterodimer dimerizes with the GDF15 mutein in the second heterodimer thereby forming the complex comprising the first heterodimer and second heterodimer;
• and
• wherein the complex reduces food intake and/or body weight in diet-induced obese mice.