Short-Term Caloric Restriction Attenuates Obesity-Induced Pro-Inflammatory Response in Male Rhesus Macaques.

White adipose tissue (WAT) hypertrophy is an essential hallmark of obesity and is associated with the activation of resident immune cells. While the benefits of caloric restriction (CR) on health span are generally accepted, its effects on WAT physiology are not well understood. We previously demonstrated that short-term CR reverses obesity in male rhesus macaques exposed to a high-fat Western-style diet (WSD). Here, we analyzed subcutaneous WAT biopsies collected from this cohort of animals before and after WSD and following CR. This analysis showed that WSD induced adipocyte hypertrophy and inhibited ß-adrenergic-simulated lipolysis. CR reversed adipocyte hypertrophy, but WAT remained insensitive to ß-adrenergic agonist stimulation. Whole-genome transcriptional analysis revealed that ß3-adrenergic receptor and de novo lipogenesis genes were downregulated by WSD and remained downregulated after CR. In contrast, WSD-induced pro-inflammatory gene expression was effectively reversed by CR. Furthermore, peripheral blood monocytes isolated during the CR period exhibited a significant reduction in the production of pro-inflammatory cytokines compared to those obtained after WSD. Collectively, this study demonstrates that short-term CR eliminates an obesity-induced pro-inflammatory response in WAT and peripheral monocytes.

De novo vitamin D supplement use post-diagnosis is associated with breast cancer survival.

PURPOSE: Experimental laboratory data have indicated a protective effect of vitamin D on breast cancer progression, while epidemiological evidence is growing. Using pharmacy claims data, this study investigates the association between vitamin D supplement use initiated after a breast cancer diagnosis and associated mortality. METHODS: Women aged 50-80 years with a record of invasive breast cancer were identified on the National Cancer Registry Ireland database (n = 5417). Initiation of de novo vitamin D post-diagnosis was identified from linked national prescription data (n = 2581, 49%). Multivariate Cox proportional hazards models were used to estimate adjusted HRs (95% CIs) for breast cancer-specific mortality. RESULTS: There was a 20% reduction in breast cancer-specific mortality in de novo vitamin D users (modelled as a time-varying variable) compared to non-users (HR 0.80; 95% CI 0.64-0.99, p = 0.048) and the reduction was greater at 49% (HR 0.51; 95% CI 0.34-0.74, p < 0.001), if vitamin D was initiated soon after the breast cancer diagnosis (within 6 months). CONCLUSIONS: In this large national breast cancer cohort, de novo vitamin D use post-diagnosis was found to be associated with a reduction in breast cancer-specific mortality. Vitamin D, therefore, has the potential as a non-toxic and inexpensive agent to improve survival in breast cancer patients. Findings support the need for RCTs exploring the effect of vitamin D supplementation on breast cancer survival.

Evidence for the use of glomerulomegaly as a surrogate marker of glomerular damage and for alpha-linolenic acid-rich oils in the treatment of early obesity-related glomerulopathy in a diet-induced rodent model of obesity.

Obesity-related glomerulopathy (ORG) is a unique and emerging condition that can lead to renal failure. Early detection, aided by an earlier diagnostic marker, would improve patient outcomes; this could be facilitated by an accurate model. Such a model would be useful to examine interventions like dietary fatty acids, which are known to influence renal diseases in later stages. In this study, obese-prone rats were provided high-fat (55% of energy) diets for 12 weeks to generate a model of diet-induced obesity. The rats were subsequently provided dietary oils with various levels of alpha-linolenic acid (ALA) and linoleic acid (LA) for 8 weeks, as follows: (g ALA:LA per 100 g oil): canola/flax (20:18), canola (8:18), soy (9:53), high-oleic canola/canola (5:16), high-oleic canola (2:15), lard/soy (1:8), and safflower (0.2:73). The model developed obesity, glomerulomegaly, proteinuria, and scarce glomerular damage with an indolent course. Morphometry and histology revealed glomerulomegaly as the first renal structural alteration. The utility of this marker as a predictor for the presence of ORG and renal injury was evidenced by its correlation to visceral adiposity (p < 0.0001, r = 0.44), proteinuria (p < 0.0001, ρ = 0.55), change in proteinuria (p = 0.0092, ρ = 0.42), and glomerular damage (p < 0.0001, ρ = 0.48). Renal triglyceride ALA:LA was strongly correlated with dietary ALA:LA (p < 0.0005, ρ = 0.96), and inversely associated with mean glomerular volume (p = 0.02, ρ = -0.82). The diet-induced obese model accurately represents early ORG, and implicates glomerulomegaly as an early surrogate diagnostic marker. Early intervention with ALA-rich dietary oils slowed glomerular enlargement; these findings warrant further clinical investigation to promote optimal patient outcomes.

Effect of dietary salt restriction on tubular hypertrophy in rats with early-stage chronic renal failure.

OBJECTIVE: Because salt restriction minimizes the occurrence of glomerular hypertrophy and tubular damage, we examined the effect of such restriction in rats with chronic renal failure (CRF). MATERIAL AND METHODS: Male Sprague-Dawley rats were fed either a low-salt rat chow (65 mg sodium/100 g) or a normal salt diet (390 mg sodium/100 g) and underwent either 4/5 nephrectomy or a sham operation. Thus, there were four study groups (10 rats in each): a low-salt nephrectomy group (L-Nx); a normal diet nephrectomy group (N-Nx); a low-salt sham operation group (L-S); and a normal diet sham operation group (N-S). At the end of 8 weeks, all the rats were killed. RESULTS: Urinary sodium output, urinary protein excretion and blood pressure in L-Nx were significantly decreased in comparison to the values in N-Nx. Body weight, urine volume and glomerular filtration rate were similar between L-Nx and N-Nx. Histologically, the planar area of glomeruli and the smallest diameter of the proximal tubules in L-Nx were significantly reduced in comparison to those in N-Nx: 8.8+/-0.3 x 10(-3) vs 9.7+/-0.3 x 10(-3) mm2 (p < 0.01) and 6.7+/-0.1 x 10(-2) vs 7.4+/-0.1 x 10(-2) mm (p < 0.01). There were no statistically significant differences between L-S and N-S with the exception of urinary sodium output. CONCLUSION: Salt restriction in nephrectomized rats minimized the occurrence of proximal tubular hypertrophy independently of renal function. This suggests that salt restriction directly delays the occurrence of both tubular hypertrophy and glomerular hypertrophy in the presence of CRF.

Prevention of 11-deoxycorticosterone-salt-induced glomerular hypertrophy and glomerulosclerosis by dietary phosphate binder.

The effects of dietary phosphate binder on deoxycorticosterone (DOC)-salt-hypertensive rats were examined. DOC-treated and non-DOC-treated rats were fed the diet either with or without phosphate binder, dihydroxyaluminum aminoacetate. All rats drank 1% NaCl. DOC-salt-treated rats without binder demonstrated marked glomerular hypertrophy, many globally sclerosed glomeruli, severe proteinuria, focal cardiac fibrosis, and splenomegaly. A significant reduction of glomerular hypertrophy, glomerulosclerosis, severity of proteinuria, splenomegaly, and the myocardial lesion took place when the DOC-salt-treated rats were given phosphate binder. The globally sclerosed glomeruli exhibited remarkable hypertrophy while structurally preserved glomeruli showed little evidence of enlargement. The plasma phosphate level was low in rats with dietary phosphate binder. In conclusion, the dietary phosphate binder ameliorated glomerular hypertrophy, glomerulosclerosis, proteinuria, myocardial fibrosis, and splenomegaly occurring in DOC-salt-treated rats. The data indicated that there was an association between glomerular hypertrophy and glomerulosclerosis in this model. The exact mechanisms of action of the phosphate binder, however, remain far from clear.