Inflammation and Metabolism of Influenza-Stimulated Peripheral Blood Mononuclear Cells From Adults With Obesity Following Bariatric Surgery.

BACKGROUND: Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism. METHODS: We studied inflammation and cellular metabolism of peripheral blood mononuclear cells (PBMCs) isolated from individuals with obesity relative to lean controls. We also investigated if impairments to PBMC metabolism were reversible upon short-term weight loss following bariatric surgery. RESULTS: Obesity was associated with systemic inflammation and poor inflammation resolution. Unstimulated PBMCs from participants with obesity had lower oxidative metabolism and adenosine triphosphate (ATP) production compared to PBMCs from lean controls. PBMC secretome analyses showed that ex vivo stimulation with A/Cal/7/2009 H1N1 influenza led to a notable increase in IL-6 with obesity. Short-term weight loss via bariatric surgery improved biomarkers of systemic metabolism but did not improve markers of inflammation resolution, PBMC metabolism, or the PBMC secretome. CONCLUSIONS: These results show that obesity drives a signature of impaired PBMC metabolism, which may be due to persistent inflammation. PBMC metabolism was not reversed after short-term weight loss despite improvements in measures of systemic metabolism.

Efficacy of Targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose-response curves and effects on proliferation and apoptosis.

Various aspects of the chemopreventive and chemotherapeutic properties of the RXR receptor agonist Targretin (LGD 1069) were examined in the methylnitrosourea (MNU)-induced model of mammary cancer. The administration of Targretin at dose levels of 60, 20 or 6.7 mg/kg body wt/day by gavage decreased the number of mammary tumors by 96, 85 and 78%, respectively. When Targretin was administered in the diet at 92 and 275 mg/kg diet cancer multiplicities were reduced by 78 and 92%, respectively. A wider range of dietary doses of Targretin at 15, 50 and 150 mg/kg diet reduced the number of mammary tumors by 38, 55 and 70%, respectively. Treatment of rats with different regimens of Targretin (250 mg/kg diet) yielded cancer multiplicities of 4.3 for non-treated rats, 0.5 for rats treated continuously with Targretin, 2.1 for rats treated with Targretin for 8 weeks followed by 10 weeks of the control diet and 1.6 for rats treated with Targretin alternating 3 days on and 4 days off. Targretin was also examined as a therapeutic agent by treating rats with at least one palpable mammary tumor for 5 weeks. A high dose of Targretin (272 mg/kg diet) caused partial or complete regression of approximately 65% of the cancers over this time period. In contrast, in animals treated with 15 mg Targretin/kg diet only 1 of 12 cancers showed significant regression. Finally, the effect of a limited exposure to Targretin (7 days) on cell proliferation and apoptosis in small mammary tumors was determined. Targretin at 150 mg/kg diet strongly decreased proliferation (75%) and increased apoptosis (300%), while a lower dose of Targretin (15 mg/kg diet, which still prevented 30% of cancers) had no effect on apoptosis but did decrease cell proliferation. Determination of serum IGF1 levels showed that treatment of rats with highly effective doses of Targretin at 272 mg/kg diet or at 60 or 20 mg/kg body wt/day by gavage caused significantly decreased serum IGF1 levels.