The development of insulin resistance, describing the progressive inability of metabolic tissues to properly respond to this endocrine signal, represents a central component of the etiology of type 2 diabetes. While this commonly occurs under obesity conditions, also other disease conditions are associated with insulin resistance, like the wasting syndrome associated with different cancer diseases also known as cancer cachexia. In contrast to obesity, cancer cachexia is characterized by a negative energy balance and progressive loss of skeletal muscle and adipose tissue, which negatively affects quality of life, efficacy of tumor treatment and eventually survival of cancer patients. Despite this clinical significance, effective therapeutic measures to counteract cancer cachexia are still lacking. Treatments improving insulin sensitivity under cachectic conditions could counteract tissue wasting through the induction of anabolic signaling. Studies in our lab demonstrated that the hepatocyte-specific inactivation of transcription factor Transforming growth factor beta-1-stimulated clone 22 D4 (TSC22D4) led to a marked improvement in systemic insulin sensitivity in diabetic mice, including induced insulin action in skeletal muscle and adipose tissue . Strikingly, hepatic TSC22D4 expression levels were also dramatically elevated in livers of cancer cachectic mice and correlated with the degree of weight loss , indicating that inhibition of hepatic TSC22D4 could represent a promising approach for insulin sensitization therapy in cancer cachexia.
Insulin sensitization therapy in cancer cachexia
We will test the potential of insulin sensitization therapy through inhibition of hepatic TSC22D4 inhibition in mouse models of colon and pancreatic cancer-associated cachexia. Different in vivo approaches are intended to achieve liver-specific inhibition of TSC22D4 using a previously established adeno-associated virus (AAV) system [1, 2], systemic application of GalNAC-conjugated siRNAs as well as genetic liver-specific TSC22D4 knockout. We will assess insulin sensitivity and glucose tolerance before tumor cell implantation and upon induction of cachexia, complemented by extensive metabolic and body composition phenotyping. Technical support for in vivo metabolic analyses will be provided by collaborators at the Alberta Diabetes Institute. Complementary in vitro experiments will focus on the functional characterization of hepatic TSC22D4 target genes in mediating downstream effects on insulin action.
 Ekim Ustunel B, Friedrich K, Maida A, Wang X, Krones-Herzig A, Seibert O, Sommerfeld A, Jones A, Sijmonsma TP, Sticht C, Gretz N, Fleming T, Nawroth PP, Stremmel W, Rose AJ, Berriel-Diaz M, Bluher M, Herzig S (2016) Control of diabetic hyperglycaemia and insulin resistance through TSC22D4. Nat Commun 7:13267.
 Jones A, Friedrich K, Rohm M, Schafer M, Algire C, Kulozik P, Seibert O, Muller-Decker K, Sijmonsma T, Strzoda D, Sticht C, Gretz N, Dallinga-Thie GM, Leuchs B, Kogl M, Stremmel W, Diaz MB, Herzig S (2013) TSC22D4 is a molecular output of hepatic wasting metabolism. EMBO Mol Med 5 (2):294-308.