Adiponectin is a protein hormone with remarkable remedial activities against most obesity-related disorders, where its otherwise high serum level is drastically reduced. This downregulation is partly caused by obesity-induced endoplasmic reticulum (ER) stress, whereupon adiponectin is aberrantly retained by ER chaperones such as Erp44. We aim to develop biotherapeutics by discovering agents that activate endogenous release of adiponectin from intracellular storage to replenish serum levels. Our preliminary results show that designed cell-penetrating peptides derived from the Erp44 binding motifs of client proteins can modulate in vivo oligomeric composition and secretion of the insulin-sensitizing high-molecular-weight (HMW) isoform of adiponectin. Driven by this finding, we aim to progressively optimize peptide reagents that will aid development of peptide-based biotherapeutics for the treatment of obesity related diseases. Such compounds could potentially replace currently used drugs for enhancing adiponectin production that are broad-acting and have severe side effects.