Date of Award


Document Type

Open Access Dissertation


Exercise Science

First Advisor

James Carson


Cachexia is a multifactorial syndrome that manifests during the advanced stage of chronic diseases and is characterized by a progressive loss of body mass sustained by underlying inflammation. The ApcMin/+ mouse is an established model of cachexia that exhibits a gradual loss of body mass correlating with increasing tumor burden and plasma IL – 6 levels. Moreover it also mimics other secondary characteristics observed in cachectic patients like splenomegaly, elevated plasma endotoxin levels, gut barrier dysfunction, hypogonadism and an overall hypermetabolic state. Liver controls the energy metabolism in the body by regulating glucose and lipid metabolism, glycogen storage, filtration of toxins from the portal blood, secretion of essential plasma protein like albumin and other acute phase proteins. As cachexia development results from sustained elevated energy demands, it can be speculated that liver might play a role in development of cachexia progression. The purpose of this study thus was to examine the role of chronic inflammation on liver function in the ApcMin/+ model of cancer cachexia. For this study liver function was studied using hepatic metabolic markers, inflammatory markers and markers of anabolic signaling. Specific Aim1 examined if liver function is altered with cachexia progression in the ApcMin/+ mouse. We report that liver function is altered by upregulation ER stress protein in non – cachectic mice. Non – cachectic mice also upregulate liver STAT- 3 phosphorylation along and suppression of liver gluconeogenic enzyme transcription.

v However, the liver maintains stores glycogen stores, Akt/mTOR/S6 signaling expression and does not initiate a NF - B or acute phase dependent immune response. However cachexia progression, sustains activation of ER stress pathways leading to inhibition of protein synthesis marker S6 phosphorylation and activation of the apoptotic marker CHOP. Severely cachectic mice exhibit inhibition of proteins associated with cell survival like Akt, ERK and NF - B. This is accompanied by an elevated STAT-3 and haptaglobin levels, but suppressed JNK expression in the liver. However, histological analysis of the cachectic liver shows a regenerative and inflammatory pathology post injury. Severely cachectic mice also show depleted liver glycogen reserves along with upregulation of enzymes regulating gluconeogeneic and glycolytic process. These results indicate the cachexia progression leads to liver dysfunction by elevating transcription of enzymes regulating glucose flux, acute phase protein response and inhibition of anabolic and survival pathways in the IL – 6 dependent ApcMin/+ model. Specific Aim 2 was targeted towards the inhibition of IL – 6 signaling to attenuate chronic inflammation in the ApcMin/+ mouse. Aim 2.1 used pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor for NF-B and STAT-3 phosphorylation, to suppress systemic inhibition in the ApcMin/+ mouse. PDTC administration attenuated body weight loss, fat loss and liver lipid content in the cachectic mouse. Though PDTC did not attenuate total polyp counts, it did suppress polyp growth by suppressing total number of large polyps in the intestine. There was an attenuation of liver metabolic markers by suppression of PEPCK mRNA and sparing of liver glycogen stores in the PDTC treated mice. Interestingly though liver PFK expression increased further with PDTC administration in the cachectic ApcMin/+. Attenuation of metabolic markers was seen independent of liver inflammation as liver STAT- 3 and haptaglobin expression remained elevated post treatment. PDTC treatment also did not affect the dysregulated Akt/mTOR/S6 signaling in the liver. Aim 2.2 used the trans – IL – 6 inhibitor sFcgp130 to attenuate liver dysfunction in the ApcMin/+. sFcgp130 administration attenuated body weight loss and fat loss in the severely cachectic ApcMin/+ mouse, but had no effect on total lean mass. sFcgp130 treated ApcMin/+ did not attenuate percentage of large tumors in the intestine but it did inhibit plasma IL – 6 levels. However, liver STAT-3 and haptaglobin levels were sustained independent of IL – 6. There was an increase in the mRNA levels of hepatic PEPCK indicating an upregulation of liver gluconeogenic response which could be possible reason for depleted liver glycogen stores in the sFcgp130 treated mice. Inhibition of trans – signaling did not attenuate hepatic suppression of the Akt, NF-B or S6 phosphorylation. Overall these results indicate that liver dysfunction during cachexia progression is independent of the IL – 6 signaling pathway. Aim 3 of this study examined the role of antibiotic treatment on cachexia progression in the ApcMin/+ mouse. The purpose of the antibiotic treatment was to suppress endotoxin mediated inflammatory response in the severely cachectic ApcMin/+ mouse. Administration of the antibiotic treatment attenuated splenomegaly and mesenteric lymph node swelling the ApcMin/+ mouse, indicating suppression of immune proliferation. However, this suppression of immune cell proliferation was not sufficient to suppress hepatic STAT-3 or haptaglobin levels. Surprisingly even plasma endotoxin levels remained elevated in the antibiotic treated ApcMin/+ mouse. Antibiotic treatment had no effect of hepatic NF-B/MMP2 or Akt/S6 pathway. Overall these results demonstrate that liver dysfunction is observed with cachexia progression in the ApcMin/+ mouse and this dysfunction is independent of plasma IL – 6 and factors affecting splenomegaly.

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