Voluntary physical activity abolishes the proliferative tumor growth microenvironment created by adipose tissue in animals fed a high fat diet.

The molecular mechanisms behind the obesity-breast cancer association may be regulated via adipokine secretion by white adipose tissue. Specifically, adiponectin and leptin are altered with adiposity and exert antagonistic effects on cancer cell proliferation. We set out to determine whether altering adiposity in vivo via high fat diet (HFD) feeding changed the tumor growth supporting nature of adipose tissue and whether voluntary physical activity (PA) could ameliorate these HFD-dependent effects. We show that conditioned media (CM) created from the adipose tissue of HFD fed animals caused an increase in the proliferation of MCF7 cells compared with cells exposed to CM prepared from the adipose of lean chow diet fed counterparts. This increased proliferation was driven within the MCF7 cells by an HFD-dependent antagonism between AMP-activated protein kinase (AMPK) and protein kinase B (Akt) signaling pathways, decreasing p27 protein levels via reduced phosphorylation at T198 and downregulation of adiponectin receptor 1 (AdipoR1). PA can ameliorate these proliferative effects of HFD-CM on MCF7 cells, increasing p27(T198) by AMPK, reducing pAkt(T308), and increasing AdipoR1, resulting in cell cycle withdrawal in a manner that depends on the PA intensity. High physical activity (>3 km/day) completely abolished the effects of HFD feeding. In addition, AdipoR1 overexpression mimics the effects of exercise, abolishing the proliferative effects of the HFD-CM on MCF7 cells and further enhancing the antiproliferative effects of PA on the HFD-CM. Thus voluntary PA represents a means to counteract the proliferative effects of adipose tissue on breast cancers in obese patients.

The direct and indirect effects of corticosterone and primary adipose tissue on MCF7 breast cancer cell cycle progression.

BACKGROUND: Breast cancer is the second leading cause of cancer-related mortality in women. Glucocorticoids (GCs) have the potential to directly affect breast cancer or indirectly via changes to the tumor growth microenvironment a breast cancer is exposed to. The role of GCs in breast cancer progression by direct and indirect means are not fully understood. AIM: To study the direct and indirect effects of GCs on breast cancer cell cycle regulation. METHODS: MCF7 breast cancer cells were incubated with increasing concentrations of corticosterone (CORT) to investigate the direct effects. In addition, MCF7 cells were cultured in conditioned media (CM) from primary adipose tissue excised from CORT-supplemented lean and obese male rats. RESULTS: CORT alone resulted in dose-dependent increases in p27 and hypophosphorylated retinoblastoma protein (Rb) which was accompanied by a reduction in the number of cells in S-phase. CM prepared from adipose tissue overrode these direct CORT effects, suggesting that the tumor growth microenvironment created in the CM dominates MCF7 cell cycle regulation. CONCLUSIONS: The direct inhibitory effects of CORT on cancer cell cycle progression are largely limited by the hormone's effects on adipose tissue biology.

Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity.

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7  h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48  h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding.

Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired ß-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.