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<p>Obesity is associated with a state of chronic, low-grade inflammation that contributes to the development of insulin resistance. Exercise is known to improve insulin resistance, and emerging evidence suggests that exercise also reduces adipose tissue inflammation. However, the relationship between exercise and inflammation has not been separated from the confounding effect of weight loss. The objectives of this study were to 1) determine whether high-intensity interval training (HIT) improves insulin sensitivity in obese mice independent of weight loss and 2) assess the effect of exercise on the relationship between adipose tissue inflammation and insulin sensitivity.</p> <p>C57BL/6 mice were assigned to one of three groups: a control, chow diet (Chow), 12 weeks of high-fat diet with no exercise (HFD Sed), or 6 weeks of high-fat diet feeding followed by an additional 6 weeks of HIT (HFD Ex). In HFD-induced obese mice, HIT had no effect on body mass, epididymal fat mass, adiposity, or adipocyte size. HIT also did not alter adipose tissue inflammation, macrophage infiltration, or adipose tissue macrophage polarization/inflammation. Nevertheless, when compared to HFD Sed mice, HIT resulted in lower fasting insulin levels and improved glucose tolerance and insulin sensitivity.</p> <p>In conclusion, these finding demonstrate that HIT improves whole-body insulin sensitivity and glucose homeostasis independent of changes in body mass or adipose tissue inflammation. The benefits of exercise in obese individuals are obvious; however, the mechanisms underlying the improvements in insulin sensitivity observed following chronic, HIT remain to be elucidated.</p> / Master of Science (MSc)

<p>In obesity, nonalcoholic fatty liver disease (NAFLD) has been associated with the development of hepatic insulin resistance. Acetyl coA carboxylase (ACC), which exists as two separate isoforms (ACC1 and ACC2), is an important metabolic enzyme which controls the production of the metabolic intermediate malonyl coA, and hence, fat metabolism. AMP-activated protein kinase (AMPK) has been shown to inhibit ACC activity by phosphoryating ACC1 at Ser79 and ACC2 at Ser221. The objectives of this were to determine the physiological importance of AMPK phosphorylation of ACC as it relates to the development of NAFLD and insulin resistance.</p> <p>We examined the metabolic phenotype of C57Bl6 mice with a targeted ACC1 Ser79 to Ala and ACC2 Ser221 to Ala double knock-in mutation (ACC DKI), which would inhibit AMPK phosphorylation of ACC and compared them to wild-type (WT) mice. Basic body characteristics, assessment of insulin sensitivity, and assessment of liver steatosis were used.</p> <p>ACC DKI body mass and energy expenditure were not different compared to WT. Liver ACC activity and malonyl coA were higher in ACC DKI mice. The livers of ACC DKI mice displayed greater triacylglycerol accumulation and aggregation of neutrophils. ACC DKI mice were insulin resistant as shown by: higher fasting blood glucose and insulin, glucose and insulin intolerance, liver insulin resistance, and impaired insulin-stimulated glucose disposal rate.</p> <p>In summary, we have shown that the phosphorylation of ACC1 Ser79 and ACC2 Ser221 is critical for maintaining ACC activity and malonyl coA levels in the liver. The dysregulation of this pathway results in liver fat accumulation and the development of insulin resistance. These studies demonstrate that AMPK phosphorylation of ACC is essential for maintaining metabolic homeostasis.</p> / Master of Science (MSc)

<p>The association between low birth weight at <em>term </em>birth and an increased risk for insulin resistance (IR) in adulthood is well established. Less is known about this association in those born markedly <em>preterm</em>. Lower birth weights are more prevalent among individuals born preterm. We compared and examined determinants of IR in adults born preterm with extremely low birth weight (ELBW; birth weight</p> / Master of Health Sciences (MSc)

Indiana University-Purdue University Indianapolis (IUPUI) / While depression is a risk factor for type 2 diabetes, little is known about the effect of depression treatment on diabetes risk markers. Using data from the recently completed eIMPACT trial (NCT02458690, supported by R01 HL122245), I examined if depression intervention improves diabetes risk markers and if improvements in somatic depressive symptoms mediate potential intervention effects. 216 participants (primary care patients ≥50 years with depression and elevated cardiovascular disease risk from a safety net healthcare system) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care intervention involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants; n=107) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and affiliated psychiatrists; n = 109). Given my focus on diabetes risk, I excluded participants who did not attend the post-treatment visit (n = 17) or who had a diabetes history at pre-treatment (n = 73), leaving a final sample of 126 (n=66 intervention, n=60 usual care; Mage = 58 years, 79% women, 50% Black, 47% with income <$10k/year). I computed depressive symptom severity variables from the Hopkins Symptom Checklist-20 (SCL-20) items: hyperphagia (“overeating” item), poor appetite (“poor appetite”), hypersomnia (“sleeping too much”), disturbed sleep (“sleep that is restless or disturbed”) and SCL-15 (mean of items not pertaining to appetite or sleep). I calculated insulin resistance from fasting plasma glucose and insulin using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)-2 calculator, body mass index (BMI) from measured height and weight, and plasma concentrations of high-sensitivity C-reactive protein (hsCRP), leptin, and ghrelin using ELISA kits. Parallel mediation analyses revealed that 12 months of modernized collaborative care for depression improved both directions of sleep symptoms but did not improve poor appetite or hyperphagia – the somatic symptom most consistently linked with increases in HOMA-IR, BMI, hsCRP, and leptin. Of the five cardiometabolic biomarkers examined, the eIMPACT intervention decreased only hsCRP and ghrelin. There were no intervention effects on HOMA-IR, BMI, or leptin. In addition, no somatic depressive symptoms mediated intervention effects on the cardiometabolic biomarkers, nor did race moderate any mediation effects. Further research is warranted to determine best practices for targeting hyperphagia and reducing cardiometabolic disease risk among people with depression.

Objective Human white adipose tissue (AT) is a metabolically active organ with distinct depot- specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism. Design Mesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR. Results While mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot- specific differences with epiAT showing the highest expression levels. Conclusion Multi- omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.

Obstructive sleep apnea syndrome (OSAS), a chronic respiratory disorder affecting as many as 1 in 5 adults, is associated with repetitive collapse of the upper airway during sleep and results in fragmented sleep and intermittent periods of hypoxia and hypercapnia. If left untreated, OSAS increases the risk for hypertension, insulin resistance, metabolic syndrome (MetS) in a manner that is independent of obesity in mid-adulthood. However, it is still unknown if evidence of these relationships is apparent in young adults with OSAS who are otherwise healthy and free of other chronic comorbidities. Objectives: To determine if functional and biochemical evidence of insulin resistance, MetS, and vascular endothelial dysfunction (VED) exists in young, overweight men with OSAS and if the combined effects of obesity and OSAS augments the evidence of chronic disease pathogenesis beyond the effects of obesity alone. Subjects: Subjects were 12 overweight men with OSAS (age = 22.8 ± 0.8; BMI = 32.4 ± 1.0; apnea-hypopnea index (AHI) = 25.4 ± 5.4), 17 overweight men without OSAS (age = 22.5 ± 0.7; BMI = 31.6 ± 1.1; AHI = 2.2 ± 0.3), and 18 normal weight men without OSAS (age = 21.1 ± 0.5; BMI = 22.4 ± 0.4; AHI = 1.9 ± 0.3). Methods: Subjects were evaluated for OSAS using an unsupervised, portable polysomnography test. Total fat and central abdominal fat (CAF) were assessed using dual energy x-ray absorptiometry (DEXA). Fasting blood samples were used to quantify biochemical markers for insulin resistance (glucose, insulin, adiponectin, IL-6, and TNF-á) and endothelial dysfunction (CRP, VEGF, and VEGFR2) using ELISA, RIA, and flow cytometry. MetS was defined according to Adult Treatment Panel III (ATP III) clinical standards. Triglycerides, HDL cholesterol, and glucose were measured using a commercial lipid panel. Resting blood pressure was obtained manually via auscultation. VED was measured via strain gauge plethysmography, with endothelium-dependent vasodilatation being assessed from forearm reactive hyperemia after a 5-minute period of upper arm occlusion. Statistics: One-way ANOVA was used to determine group differences in variables. Two-way ANOVA was used to evaluate group x time interactions during the 2-minute recovery period following upper arm occlusion. Pearson partial correlation was used to assess relationships between continuous variables, with analyses being controlled for CAF or OSAS severity. Spearman correlation was used to assess relationships between number of MetS components present and both indices of adiposity and OSAS severity. Stepwise multiple linear regression analysis was used to determine significant predictors of OSAS severity, insulin resistance, components of the MetS, and endothelial dysfunction. Results: Overweight subjects with OSAS had more CAF, higher fasting triglycerides, and lower serum adiponectin concentrations than both overweight and normal weight non-apneic controls. Furthermore, fasting triglycerides were directly correlated to OSAS severity, even after the influence of central abdominal fat was removed. OSAS severity was an independent predictor of triglyceride levels, and vice versa. Insulin resistance, leptin, insulin, and CRP were all higher in overweight subjects than controls, but no further differences were attributable to severity of OSAS. No differences in IL-6, TNF-á, ADMA, and expression of VEGFR2 were noted between any groups. No group or group x time interaction differences existed in regards to postocclusive reactive hyperemia responses. Conclusions: Young men with OSAS exhibit several unique anthropometric and biochemical abnormalities that may indicate early pathogenesis of or increased risk for future development for cardiovascular and metabolic disorders. Identification and treatment of OSAS at this age may be critical to prevent the onset and progression of these chronic disorders. / Ph. D.