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Objective Obesity is a major public health challenge, and the US military veteran population is disproportionately affected. Using deidentified records from a local weight management clinic and a national clinical data repository, obesity pharmacotherapy use and effectiveness for weight loss and obesity comorbidities in this vulnerable population were assessed. Methods During the initial year of the local clinic, 43 records with monthly follow-up of MOVE! lifestyle intervention augmented by obesity pharmacotherapy were found. Nationally, more than 2 million records of prescribed obesity pharmacotherapy compared with metformin as control were identified. Records with detailed documentation of weight trends from 1 year before to 1 year after the prescription date for further analysis were selected for review. Results The most commonly prescribed medications in the local clinic were metformin, liraglutide, and combination phentermine/topiramate. On average, weight loss of -4.0 ± 2.1 kg over the initial 6-month intervention was observed. In the national cohort, 577,491 records with an obesity or control metformin prescription and adequate weight documentation were identified. The most effective pharmacotherapy in the national cohort was phentermine/topiramate (-0.0931 ± 0.0198 kg/wk difference), followed by liraglutide, lorcaserin, and orlistat. Conclusions Obesity pharmacotherapy is effective in achieving clinically meaningful weight loss in veterans as part of an integrated care approach.

Introduction: The incidence of obesity and its comorbidities is increasing at an alarming rate in US and around the globe. Our previous studies showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and insulin resistance (IR), as global Ager (gene encoding RAGE) and adipocyte-specific Ager- deleted mice fed a high fat diet (HFD) showed protection from weight gain and IR. However, the role of Ager deletion in mice with established obesity, switched to low fat diet has not been tested. We hypothesize that temporal adipocyte-specific deletion of Ager in obese mice could enhance weight loss and improves glucose homeostasis. Methods: Mice with conditional adipocyte-specific Ager deletion were generated by breeding Ager flox/flox mice with AdipoQ ERT2 Cre recombinase mice resulting in Ager flox/flox / AdipoQ ERT2 Cre (+) and Cre (-) animals. Mice were fed HFD (60% kcal/fat) for 20 weeks starting at 8 weeks of age to establish obesity and were then treated with tamoxifen (TAM) (75 mg/kg per day x 3 alternative days) to induce deletion of Ager . After 4 weeks of TAM treatment, mice were switched to standard chow for 7 weeks and body weight was monitored regularly. Fasting glucose, insulin and glucose tolerance was measured. Results: After 7 weeks of switching to standard chow following TAM, Cre (+) lost significantly more body weight whereas Cre (-) mice showed no significant weight loss over 7 weeks. Furthermore, Cre (+) mice exhibited significantly higher food intake, lower fasting glucose, lower epididymal and inguinal white adipose tissue weights, and improved glucose and insulin tolerance compared to Cre (-) mice. Conclusions: Temporal adipocyte-specific deletion of Ager in mice with established obesity promotes weight loss and improves glucose homeostasis. RAGE may act as a novel therapeutic target in obesity.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti‐inflammatory and insulin‐sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long‐term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety‐ and depression‐like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ‐independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan., In this manuscript, we show that chronic use of low doses of antidiabetic drugs that target the nuclear receptor PPARgamma preserves metabolic organ function and cognitive abilities and decreases depression‐ and anxiety‐like symptoms. Through functional, histological, and molecular analyses, we demonstrated that treated mice have improved adipose tissue homeostasis, reduced sarcopenia, decreased inflammation, and improved mitochondrial functionality. In addition, our longevity studies demonstrated lifespan extension in mice and increased survival in humans in response to TZD. These data support the possible long‐term use of low doses PPARgamma ligands to counteract aging.

Background: Overweight and obesity are major health burdens, and the military veteran population may be disproportionately affected. Multiple new pharmacologic agents and combinations have been approved by the FDA for use in medical weight management. Using deidentified records from our local interdisciplinary weight management clinic and a national clinical data repository, we assessed obesity pharmacotherapy use and its real-world effectiveness for weight loss and improvement of comorbid metabolic parameters in this vulnerable population. Methods: During the initial year of the local weight management clinic, we found over 50 records with monthly followup of lifestyle intervention augmented by obesity pharmacotherapy. In the national clinical data repository, we identified over 2 million records for unique individuals prescribed bupropion-naltrexone, liraglutide, lorcaserin, orlistat, or phentermine-topiramate, and metformin considered as a control prescription. We selected records with detailed documentation of weight trends from 1 year before to 1 year after first prescription date for further analysis. Results: The most commonly prescribed medications in our local weight management clinic were metformin, liraglutide, orlistat, and combination phentermine/topiramate. On average, we observed −4.0 ± 2.1 kg weight loss over the initial 6-month intervention in records that completed at least 3 visits within this period. In the national database, over 800,000 records for an obesity or control metformin prescription provided adequate weight documentation to compare weight slopes during the year before and after the prescription start date. Records for metformin prescriptions showed −0.04 ± 0.008 kg/week difference in weight slope over one year before versus after the prescription start date. The greatest difference in weight slope was seen with phentermine-topiramate (−0.13 ± 0.03 kg/week), followed by lorcaserin, liraglutide, bupropion-naltrexone, and orlistat. Conclusions: Our data suggests that veterans with obesity experience weight loss at 1 year follow-up when engaged with our interdisciplinary weight management clinic. Nationally, veterans with obesity experience modest weight loss when prescribed pharmacotherapy. Taken together, our two data sources provide complementary perspectives to help guide obesity pharmacotherapy in veterans with obesity.

Development of biochips containing living cells for biodetection, drug screening and tissue engineering applications is limited by a lack of reconfigurable material interfaces and actuators. Here we describe a new class of nanostructured magnetizable materials created with a femtosecond laser surface etching technique that function as multiplexed magnetic field gradient concentrators. When combined with magnetic microbeads coated with cell adhesion ligands, these materials form microarrays of 'virtual' adhesive islands that can support cell attachment, resist cell traction forces and maintain cell viability. A cell death (apoptosis) response can then be actuated on command by removing the applied magnetic field, thereby causing cell retraction, rounding and detachment. This simple technology may be used to create reconfigurable interfaces that allow users to selectively discard contaminated or exhausted cellular sensor elements, and to replace them with new living cellular components for continued operation in future biomedical microdevices and biodetectors.

The formation of focal adhesions that mediate alterations of cell shape and movement is controlled by a mechanochemical mechanism in which cytoskeletal tensional forces drive changes in molecular assembly; however, little is known about the molecular biophysical basis of this response. Here, we describe a method to measure the unbinding rate constant k(OFF) of individual GFP-labeled focal adhesion molecules in living cells by modifying the fluorescence recovery after photobleaching (FRAP) technique and combining it with mathematical modeling. Using this method, we show that decreasing cellular traction forces on focal adhesions by three different techniques--chemical inhibition of cytoskeletal tension generation, laser incision of an associated actin stress fiber, or use of compliant extracellular matrices--increases the k(OFF) of the focal adhesion protein zyxin. In contrast, the k(OFF) of another adhesion protein, vinculin, remains unchanged after tension dissipation. Mathematical models also demonstrate that these force-dependent increases in zyxin's k(OFF) that occur over seconds are sufficient to quantitatively predict large-scale focal adhesion disassembly that occurs physiologically over many minutes. These findings demonstrate that the molecular binding kinetics of some, but not all, focal adhesion proteins are sensitive to mechanical force, and suggest that force-dependent changes in this biophysical parameter may govern the supramolecular events that underlie focal adhesion remodeling in living cells.

Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets., Author Summary Heart disease remains the most common source of mortality in the American population. The Western diet has been implicated as an important factor, though the mechanisms by which high levels of dietary sugar and fat contribute to heart failure remain controversial. Here, we use the fruit fly Drosophila to explore the role of diet on progressive heart failure. We show that elevated levels of dietary sugar are sufficient to direct progressive heart failure in flies including arrhythmia, reduced fractional shortening, and aspects of fibrosis. We demonstrate the importance of multiple cellular pathways, including the hexosamine biosynthetic pathway, as important for mediating these progressive defects, suggesting a potential avenue towards therapeutics.

The formation of focal adhesions governs cell shape and function; however, there are few measurements of the binding kinetics of focal adhesion proteins in living cells. Here, we used the fluorescence recovery after photobleaching (FRAP) technique, combined with mathematical modeling and scaling analysis to quantify dissociation kinetics of focal adhesion proteins in capillary endothelial cells. Novel experimental protocols based on mathematical analysis were developed to discern the rate-limiting step during FRAP. Values for the dissociation rate constant k(OFF) ranged over an order of magnitude from 0.009+/-0.001/s for talin to 0.102+/-0.010/s for FAK, indicating that talin is bound more strongly than other proteins in focal adhesions. Comparisons with in vitro measurements reveal that multiple focal adhesion proteins form a network of bonds, rather than binding in a pair-wise manner in these anchoring structures in living cells.