Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD1VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD1VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD1VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD1VDD versus the WD group (NAS: WD1VDD 3.2 6 0.47 versus WD 1.50 6 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1b, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD1VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)c, and HO-1. Conclusion: VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes. (HEPATOLOGY 2012;55:1103-1111

Objective To utilize quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. Methods Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N=22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N=23) from the lowest tertile. In a separate postmortem study, brain slices (N=10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). Results In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P=0.01). Compared to controls, cases had longer T2 relaxation times in the right MBH (P<0.05), as well as higher BMI (P<0.05), fasting insulin concentrations (P<0.01), and HOMA-IR values (P<0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P<0.05), validating an MRI-based method for the detection of MBH gliosis in humans. Conclusions These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.

The prevalence of overweight and obesity has markedly increased during the past few decades. Stress has been suggested as one environmental factor that may contribute to the development of obesity. In this review, we discuss the role that exposure to chronic stress may play in the development of obesity, with particular attention to the effects of chronic psychosocial stress. Of particular importance is the effect that social stress has on dietary preference, food consumption, and regional distribution of adipose tissue. We present evidence from human and animal studies that links sympathetic nervous system and hypothalamic-pituitary-adrenal axis hyperactivity with visceral obesity, and that stress tends to alter the pattern of food consumption, and promotes craving of nutrient-dense “comfort foods.” Lastly, we discuss the visible burrow system, a model of chronic social stress used in our laboratory to assess the effects of social subordination on behavioral and metabolic profile.