Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity (lipotoxicity), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity (the athlete’s paradox). Despite these findings, it remains unclear whether changes in IMTG accumulation and metabolism per se influence muscle-specific and systemic metabolic homeostasis and insulin responsiveness. By mediating the rate-limiting step in triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/production of deleterious as well as essential lipid metabolites. However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal muscle remains unknown. To determine the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes in the context of obesity, we generated mice with targeted deletion or transgenic overexpression of ATGL exclusively in skeletal muscle. Despite dramatic changes in IMTG content on both chow and high-fat diets, modulation of ATGL-mediated IMTG hydrolysis did not significantly influence systemic energy, lipid, or glucose homeostasis, nor did it influence insulin responsiveness or mitochondrial function. These data argue against a role for altered IMTG accumulation and lipolysis in muscle insulin resistance and metabolic complications of obesity.

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Surgery followed by EBRT provided durable locoregional disease control with limited morbidity. Postoperative EBRT merits consideration in cases of advanced disease at high risk for locoregional recurrence.

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4098 Background: Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Determining modifiable prognostic factors may be a key step in improving outcomes of these patients with overall poor survival. Pancreatic adenocarcinoma is often associated with diabetes. Our aim is to determine whether diabetes worsens disease specific mortality in resectable pancreatic cancer patients. Methods: In this study, we reviewed 298 patients with resected pancreatic adenocarcinoma in our surgical database at MD Anderson Cancer Center between August 1992 and July 2003. Patients were classified into diabetics (N = 87) (defined as those carrying the diagnosis of diabetes (DM) at time of presentation or on long term therapy for DM) and nondiabetics (N = 211). Univariate (log-rank) and Multivariate (Cox Regression) analyses were performed. Results: Compared to nondiabetics, patients with DM had a poorer overall survival with a median survival of 19.8 vs 29.2 months (p = 0.01). On multivariate analysis, correcting for known poor prognosticators in resectable patients: staging, histologic tumor differentiation and retroperitoneal margin status, diabetes was a significant independent risk factor for increased overall mortality (OR 1.55, 95% CI 1.15–2.07, p = 0.004). Disease-specific mortality was also higher in diabetics vs. non-diabetics with a median survival of 29.87 vs. 21.47 months (OR 1.37 95% CI 1.00–1.89 p = 0.048). Stage specific mortality was also higher among diabetics. Potential etiologies will be discussed. Conclusions: Diabetes worsens disease specific and overall mortality in patients with pancreatic cancer. Diabetes may be a modifiable risk factor and should be considered while prognosticating patients with resectable pancreatic cancer. Further studies are needed to determine whether treatment of diabetes improves outcomes. No significant financial relationships to disclose.

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Severe primary hypothyroidism should be considered in the differential diagnosis of pituitary enlargement. Thyroid hormone replacement therapy should lead to regression of pituitary hyperplasia.