Immune and Metabolic Biomarkers in a Rodent Model of Spinal Cord Contusion.

STUDY DESIGN: Basic science animal research study. OBJECTIVES: Using T10 spinal contused rats, we sought to identify molecular and circulating, metabolic and immune biomarkers during the subchronic and chronic recovery periods that may inform us concerning neurorehabilitation. METHODS: Gene expression of the cord and ELISA were performed in 28 and 100 days in T10 injured rats and compared to sham-injured rats. Hundred-day injured rats were placed on either a low-fat or high-fat diet following the recovery phase. Linear regression analysis was performed between markers and locomotor score, body weight, body composition, and blood cholesterol and triglycerides. RESULTS: Gene expression in the thoracic cord for complement marker, C1QC, dendritic cell marker, ITGAX, and cholesterol biosynthesis genes, FDFT1, HMCGR, LDLR, and SREBP1, were significantly associated with BBB score, body weight, composition, and other metabolic parameters. Circulating levels of these proteins, however, did not vary by injury or predict the level of locomotor recovery. CONCLUSIONS: Identification of reliable circulating biomarkers that are durable and based on level of spinal injury are complicated by immune and metabolic comorbidities. Continued work is necessary to identify stable markers of disease progression.

Whole genome transcriptome analysis of the stomach resected in human vertical sleeve gastrectomy: cutting more than calories.

Vertical sleeve gastrectomy (VSG) is a surgical weight loss procedure that resects 80% of the stomach, creating a tube linking the esophagus to the duodenum. Because of the efficacy and relative simplicity of VSG, it is preferred in the United States, with VSG currently at >61% of bariatric surgeries performed. Surprisingly, there has never been a complete molecular characterization of the human stomach greater curvature's fundus and corpus. Here we compare and contrast the molecular makeup of these regions. We performed a prospective cohort study to obtain gastric tissue samples from patients undergoing elective VSG. Paired fundus and corpus samples were obtained. Whole genome transcriptome analysis was performed by RNA sequencing (N = 10), with key findings validated by qPCR (N = 24). Participants were primarily female (95.8%) and White (79.15%). Mean body mass index, body weight, and age were 46.1 kg/m2, 121.6 kg, and 43.29 yr, respectively. Overall, 432 gene transcripts were significantly different between the fundus and the corpus (P < 0.05). A significant correlation was found between the RNA sequencing dataset and qPCR validation, demonstrating robust gene expression differences between the fundus and the corpus. Significant genes included progastricsin, acidic chitinase, and gastokine 1 and 2 in both the fundus and the corpus. Of the very highly expressed genes in both regions, 87% were present in both the stomach's fundus and corpus, indicating substantial overlap. Despite significant overlap in the greater curvature gene signature, regional differences exist within the fundus and the corpus. Given that the mechanism of VSG is partly unresolved, the potential that the resected tissue may express genes that influence long-term body weight regulation is unknown and could influence VSG outcomes.

Dysregulated appetitive leptin signaling in male rodent offspring from post-bariatric dams.

Bariatric surgery produces significant positive benefits to recipients such as significant body fat loss and resolution of the various obesity-related comorbidities, such as reduced reproductive function. Females of childbearing age seek bariatric surgical remedies to improve their chance of successful pregnancy; however, limited knowledge exists on the impact of surgical weight loss to subsequently born offspring. We previously reported that circulating leptin levels were reduced in pregnant females having previously received vertical sleeve gastrectomy (VSG) in comparison to control dams having received Sham surgery. Furthermore, the levels of leptin receptors in the VSG placenta were also reduced in VSG. These data suggest a significant difference in leptin signaling during pregnancy that may produce an altered developmental environment for the offspring. Here, we investigate the adult offspring of dams having received VSG or Sham-VSG prior to pregnancy. Endogenous fasting plasma leptin levels were not different between Sham and VSG offspring. Fasting leptin receptor mRNA in the medial basal hypothalamus (MBH) was elevated in VSG offspring in comparison to Sham. Intraperitoneal administration of exogenous leptin produced reductions in acute food intake in male Sham offspring, but did not reduce food intake at any time point measured in male VSG offspring. Using Western blot, we identified elevated pSTAT3 and pSTAT3/STAT3 ratios in the MBH of post-VSG offspring in comparison to controls. Using immunohistochemistry, we found an increased number of pSTAT positive cells in the arcuate nucleus in the Sham offspring in comparison to VSG. In contrast, within the paraventricular and ventromedial nuclei in the hypothalamus of the VSG offspring had elevated numbers of pSTAT-positive cells in comparison to controls. Collectively, these data support our hypothesis that leptin signaling is dysregulated in VSG offspring and may be partially responsible for the long-term impact of maternal bariatric surgery on the metabolic health of offspring.

Energy balance following diets of varying fat content: metabolic dysregulation in a rodent model of spinal cord contusion.

Within the spinal cord injured (SCI) population, metabolic dysfunction may be exacerbated. Models of cord injury coupled with metabolic stressors have translational relevance to understand disease progression in this population. In the present study, we used a rat model of thoracic SCI at level T10 (tSCI) and administered diets comprised of either 9% or 40% butterfat to create a unique model system to understand the physiology of weight regulation following cord injury. SCI rats that recovered on chow for 28 days had reduced body mass, lean mass, and reduced fat mass but no differences in percentage of lean or fat mass composition. Following 12 weeks on either low-fat diet (LFD) or high-fat diet (HFD), SCI rats maintained on LFD did not gain weight at the same rate as SCI animals maintained on HFD. LFD-SCI had reduced feed conversion efficiency in comparison to Sham-LFD whereas tSCI-HFD were equivalent to Sham-HFD rats. Although SCI rats still maintained lower lean body mass, by the end of the study HFD-fed rats had higher body fat percentage than LFD-fed rats. Macronutrient selection testing demonstrated SCI rats had a significant preference for protein over Sham rats. Analysis of metabolic cage activity showed tSCI rats had elevated energy expenditure, despite reduced locomotor activity. Muscle triglycerides and cholesterol were reduced only in LFD-tSCI rats. These data suggest that consumption of HFD by tSCI rats alters the trajectory of metabolic dysfunction in the context of spinal cord disease progression.

Anxiety behavior and hypothalamic-pituitary-adrenal axis altered in a female rat model of vertical sleeve gastrectomy.

Surgical weight loss results in a host of metabolic changes that culminate in net positive health benefit to the patients. However, the psychological impact of these surgeries has not been fully studied. On one hand, surgical weight loss has been reported to improve standard quality of life and resolution of symptoms of depression. But on the other hand, reports of self-harm and increased ER visits for self-harm suggest other psychological difficulties. Inability to handle anxiety following surgical weight loss has alarming potential ramifications for these gastric surgery patients. In the present study, we used models of diet-induced obesity and vertical sleeve gastrectomy (VSG) to ask whether anxiety behavior and hypothalamic-pituitary-adrenal (HPA) axis gene changes were affected by surgical weight loss under two diet regimens: i.e. low-fat diet (LFD) and high-fat diet (HFD). We show reduced exploratory behavior in the open field test but increased time in the open arms of the elevated plus maze. Furthermore, we show increased plasma levels of corticosterone in female VSG recipients in the estrus phase and increased levels of hypothalamic arginine-vasopressin (avp), pro-opiomelanocortin (pomc), and tyrosine hydroxylase (th). We report reduced dopamine receptor D1 (drd1) gene in prefrontal cortex (PFC) in VSG animals in comparison to Sham. Further we report diet-driven changes in stress-relevant gene targets in the hypothalamus (oxt, pomc, crhr1) and adrenal (nr3c1, nr3c2, mc2r). Taken together, these data suggest a significant impact of both surgical weight loss and diet on the HPA axis and further impact on behavior. Additional assessment is necessary to determine whether molecular and hormonal changes of surgical weight loss are the source of these findings.