Duchenne muscular dystrophy: disease mechanism and therapeutic strategies.

Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials.

Suboptimal adherence to food restrictions requirements related to drug regimens for chronic diseases.

BACKGROUND: Oral medications for chronic conditions often involve a variety of instructions, including time of day/dosing, drug interactions, and food intake restrictions. However, the extent to which patients follow these instructions is unclear. METHODS: We surveyed patients from the US and Europe (UK, France, Germany, Italy, Spain) who were prescribed sulfonylureas (SU: glimepiride, glipizide, or gliclazide) for diabetes or levothyroxine for hypothyroidism. Patients kept a daily diary for 3-5 days documenting their adherence to three criteria: dosing regimen including time of day, warning labels including drug interactions, and food restrictions. RESULTS: A total of 421 US and 493 European patients took the study medications; 546 patients took SU and 368 took levothyroxine. Overall, 48% of patients were males; 46% were age 65 years or older. Despite most patients having received instructions on medication requirements (US 71%, EU 75%), most patients reported being only somewhat knowledgeable (US 69%; EU 71%). Adherence, measured by the proportion of the days a participant was adherent to each category out of the observational period (ranging from 3-5 days), varied by type of instruction, with the poorest adherence observed for food restriction requirements (US 34% of the observation days, EU 26%) compared to warning labels (US 77%, EU 67%) and dosing regimen (US 85%, EU 87%). CONCLUSIONS: Patients adhered to dosing and cautionary instructions across the majority of the study period but were largely non-adherent to food intake restrictions. Improved communication and increased emphasis on food intake restrictions is needed when advising patients on their medications.

Relationships between headache frequency, disability, and disability-related unemployment among adults with migraine.

BACKGROUND: Migraine is the second most common cause of disability worldwide. Understanding the relationship between migraine and employment status is critical for policymakers, as disability-related unemployment is associated with eligibility for private or governmental disability insurance payments and other associated support for those unable to work because of disability. OBJECTIVE: To assess the association between migraine frequency and selfreported employment status and overall disability in a US representative survey. METHODS: Using data from the 2019 National Health and Wellness Survey (NHWS) (Kantar Health), adults in the United States (aged 18-65 years) reporting at least 1 migraine day in the past 30 days were categorized by headache frequency: low-frequency episodic migraine (LFEM) (≤4 days/month), moderate-frequency EM (MFEM) (5-9 days/month), high-frequency EM (HFEM) (10-14 days/month), or chronic migraine (CM) (≥15 days/month). A control group of adults without migraine with similar baseline characteristics was identified by propensity score matching. Disability-related unemployment was defined as participants responding "short-term disability" or "long-term disability" to occupational status on the NHWS. The frequency of short- or long-term disability was then evaluated across headache frequency groups. In addition, participants were asked to assess migraine-related disability via the Migraine Disability questionnaire (MIDAS). RESULTS: A total of 1,962 respondents with LFEM, 987 with MFEM, 554 with HFEM, and 926 with CM were included in this analysis, along with 4,429 matched controls. Headache frequency was associated both with increased MIDAS score and with employment disability (P < 0.001); 12.3% (n = 114 of 926) of participants with CM reported employment disability, as did 4.4% (n = 86 of 1,962) of the LFEM group and 6.9% (n = 306 of 4,429) of matched controls. There was considerable discordance between the proportion of participants classified as disabled via MIDAS vs those reporting employment-related disability. CONCLUSIONS: More frequent migraine headaches are associated with a higher likelihood of self-reported short- and long-term employment disability and overall migraine-related disability, suggesting that health and economic policymakers must seek ways to maximize the employment opportunities for people living with migraine that may benefit from novel preventive treatments. DISCLOSURES: Robert E Shapiro is a research consultant for Eli Lilly and Lundbeck. Ashley A Martin and Martine C Maculaitis are employees of Cerner Enviza (formerly Kantar Health), which received payment from Lundbeck to conduct the research. Shiven Bhardwaj was an employee of Lundbeck at the time of study and manuscript development. Heather Thomson and Carlton Anderson are employees of Lundbeck. Steven M Kymes is an employee and stockholder of Lundbeck. Financial support for research conducted and manuscript preparation was provided by Lundbeck.

Cardiac Sarcomere Signaling in Health and Disease.

The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.

Sarcomere dynamics revealed by a myofilament integrated FRET-based biosensor in live skeletal muscle fibers.

The sarcomere is the functional unit of skeletal muscle, essential for proper contraction. Numerous acquired and inherited myopathies impact sarcomere function causing clinically significant disease. Mechanistic investigations of sarcomere activation have been challenging to undertake in the context of intact, live skeletal muscle fibers during real time physiological twitch contractions. Here, a skeletal muscle specific, intramolecular FRET-based biosensor was designed and engineered into fast skeletal muscle troponin C (TnC) to investigate the dynamics of sarcomere activation. In transgenic animals, the TnC biosensor incorporated into the skeletal muscle fiber sarcomeres by stoichiometric replacement of endogenous TnC and did not alter normal skeletal muscle contractile form or function. In intact single adult skeletal muscle fibers, real time twitch contractile data showed the TnC biosensor transient preceding the peak amplitude of contraction. Importantly, under physiological temperatures, inactivation of the TnC biosensor transient decayed significantly more slowly than the Ca2+ transient and contraction. The uncoupling of the TnC biosensor transient from the Ca2+ transient indicates the biosensor is not functioning as a Ca2+ transient reporter, but rather reports dynamic sarcomere activation/ inactivation that, in turn, is due to the ensemble effects of multiple activating ligands within the myofilaments. Together, these findings provide the foundation for implementing this new biosensor in future physiological studies investigating the mechanism of activation of the skeletal muscle sarcomere in health and disease.

Understanding the Burdens Associated with Huntington's Disease in Manifest Patients and Care Partners-Comparing to Parkinson's Disease and the General Population.

BACKGROUND: The study provides real-world data on the impact of Huntington's disease (HD) from the perspective of individuals with HD (IHD) and care partners (HD-CP) and contextualizes these results relative to Parkinson's disease (PD) and the general population (GP). METHODS: Cross-sectional survey of IHD and HD-CP in the US (July 2019-August 2019) conducted using the Rare Patient Voice panel. Data for individuals with Parkinson's Disease (IPD), the general population (GP), and respective care partners (PD-CP; GP-CP) came from the 2018 US National Health and Wellness Survey. Outcomes included demographics, mental health, clinical characteristics, and health-related quality of life (HRQoL). RESULTS: IHD had greater comorbid anxiety (IHD = 51.2%, IPD = 28.8%, GP = 2.0%), and HD-CP had greater comorbid anxiety (HD-CP = 52.5%, PD-CP = 28.6%, GP-CP = 19.6%) and depression (HD-CP = 65.0%, PD-CP = 29.9%, GP-CP = 19.6%), relative to other cohorts (p < 0.05). Respective of their GP cohorts, IHD exhibited lower HRQoL (EQ-5D: 0.66 ± 0.21 vs. 0.81 ± 0.17) and greater depression (PHQ-9: 11.59 ± 7.20 vs. 5.85 ± 6.71), whereas HD-CP exhibited greater depression only (PHQ-9: 6.84 ± 6.38 vs. 4.15 ± 5.58) (p < 0.001). No differences were observed between HD/HD-CP and PD/PD-CP cohorts on PHQ-9 or HRQoL. CONCLUSIONS: HD has a significant burden on patients and care partners, which is higher than GP. Notably, anxiety and depression were greater among HD vs. PD, despite similar HRQoL.

Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle.

The sarcomere is the functional unit of cardiac muscle, essential for normal heart function. To date, it has not been possible to study, in real time, thin filament-based activation dynamics in live cardiac muscle. We report here results from a cardiac troponin C (TnC) FRET-based biosensor integrated into the cardiac sarcomere via stoichiometric replacement of endogenous TnC. The TnC biosensor provides, for the first time, evidence of multiple thin filament activating ligands, including troponin I interfacing with TnC and cycling myosin, during a cardiac twitch. Results show that the TnC FRET biosensor transient significantly precedes that of peak twitch force. Using small molecules and genetic modifiers known to alter sarcomere activation, independently of the intracellular Ca2+ transient, the data show that the TnC biosensor detects significant effects of the troponin I switch domain as a sarcomere-activating ligand. Interestingly, the TnC biosensor also detected the effects of load-dependent altered myosin cycling, as shown by a significant delay in TnC biosensor transient inactivation during the isometric twitch. In addition, the TnC biosensor detected the effects of myosin as an activating ligand during the twitch by using a small molecule that directly alters cross-bridge cycling, independently of the intracellular Ca2+ transient. Collectively, these results aid in illuminating the basis of cardiac muscle contractile activation with implications for gene, protein, and small molecule-based strategies designed to target the sarcomere in regulating beat-to-beat heart performance in health and disease.

Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies.

: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.

In Vivo Calcium Imaging in C. elegans Body Wall Muscles.

The model organism C. elegans provides an excellent system to perform in vivo calcium imaging. Its transparent body and genetic manipulability allow for the targeted expression of genetically encoded calcium sensors. This protocol outlines the use of these sensors for the in vivo imaging of calcium dynamics in targeted cells, specifically the body wall muscles of the worms. By utilizing the co-expression of presynaptic channelrhodopsin, stimulation of acetylcholine release from excitatory motor neurons can be induced using blue light pulses, resulting in muscle depolarization and reproducible changes in cytoplasmic calcium levels. Two worm immobilization techniques are discussed with varying levels of difficulty. Comparison of these techniques demonstrates that both approaches preserve the physiology of the neuromuscular junction and allow for the reproducible quantification of calcium transients. By pairing optogenetics and functional calcium imaging, changes in postsynaptic calcium handling and homeostasis can be evaluated in a variety of mutant backgrounds. Data presented validates both immobilization techniques and specifically examines the roles of the C. elegans sarco(endo)plasmic reticular calcium ATPase and the calcium-activated BK potassium channel in the body wall muscle calcium regulation.

The sarco(endo)plasmic reticulum calcium ATPase SCA-1 regulates the Caenorhabditis elegans nicotinic acetylcholine receptor ACR-16.

Nicotinic acetylcholine receptors (nAChR) are present in many excitable tissues and are found both pre and post-synaptically. Through their non-specific cationic permeability, these nAChRs have excitatory roles in neurotransmission, neuromodulation, synaptic plasticity, and neuroprotection. Thus, nAChR mislocalization or functional deficits are associated with many neurological disease states. Therefore identifying the mechanisms that regulate nAChR expression and function will inform our understanding of normal as well as pathological physiological conditions and offer avenues for potential therapeutic advances. Taking advantage of the genetic tractability of the soil nematode Caenorhabditis elegans, a forward genetic screen was performed to isolate regulators of the vertebrate α7 nAChR homologue ACR-16. From this screen a novel regulator of the ACR-16 receptor was identified, the sarco(endo)plasmic reticulum calcium ATPase sca-1. The sca-1 mutant affects ACR-16 receptor level at the NMJ, receptor functionality, and synaptic transmission. Responses to pressure-ejected nicotine in sca-1 mutants are indistinguishable from wild type, which implies the ACR-16 receptors are mislocalized at the NMJ. Changes in cytosolic baseline calcium levels in sca-1 and other mutants indicates a calcium-driven regulation mechanism of the α7-like NAChR ACR-16.

"What time is my next meal?" delay-discounting individuals choose smaller portions under conditions of uncertainty.

'Dietary' delay discounting is typically framed as a trade-off between immediate rewards and long-term health concerns. Our contention is that prospective thinking also occurs over shorter periods, and is engaged to select portion sizes based on the interval between meals (inter-meal interval; IMI). We sought to assess the extent to which the length of an IMI influences portion-size selection. We predicted that delay discounters would show 'IMI insensitivity' (relative lack of concern about hunger or fullness between meals). In particular, we were interested in participants' sensitivity to an uncertain IMI. We hypothesized that when meal times were uncertain, delay discounters would be less responsive and select smaller portion sizes. Participants (N = 90) selected portion sizes for lunch. In different trials, they were told to expect dinner at 5pm, 9pm, and either 5pm or 9pm (uncertain IMI). Individual differences in future-orientation were measured using a monetary delay-discounting task. Participants chose larger portions when the IMI was longer (p < 0.001). When the IMI was uncertain, delay-discounting participants chose smaller portions than the average portion chosen in the certain IMIs (p < 0.05). Furthermore, monetary discounting mediated a relationship between BMI and smaller portion selection in uncertainty (p < 0.05). This is the first study to report an association between delay discounting and IMI insensitivity. We reason that delay discounters selected smaller portions because they were less sensitive to the uncertain IMI, and overlooked concerns about potential future hunger. These findings are important because they illustrate that differences in discounting are expressed in short-term portion-size decisions and suggest that IMI insensitivity increases when meal timings are uncertain. Further research is needed to confirm whether these findings generalise to other populations.

Fructose in Breast Milk Is Positively Associated with Infant Body Composition at 6 Months of Age.

Dietary sugars have been shown to promote excess adiposity among children and adults; however, no study has examined fructose in human milk and its effects on body composition during infancy. Twenty-five mother-infant dyads attended clinical visits to the Oklahoma Health Sciences Center at 1 and 6 months of infant age. Infants were exclusively breastfed for 6 months and sugars in breast milk (i.e., fructose, glucose, lactose) were measured by Liquid chromatography-mass spectrometry (LC-MS/MS) and glucose oxidase. Infant body composition was assessed using dual-energy X-ray absorptiometry at 1 and 6 months. Multiple linear regression was used to examine associations between breast milk sugars and infant body composition at 6 months of age. Fructose, glucose, and lactose were present in breast milk and stable across visits (means = 6.7 µg/mL, 255.2 µg/mL, and 7.6 g/dL, respectively). Despite its very low concentration, fructose was the only sugar significantly associated with infant body composition. A 1-µg/mL higher breast milk fructose was associated with a 257 g higher body weight (p = 0.02), 170 g higher lean mass (p = 0.01), 131 g higher fat mass (p = 0.05), and 5 g higher bone mineral content (p = 0.03). In conclusion, fructose is detectable in human breast milk and is positively associated with all components of body composition at 6 months of age.

Modulation of sweet preference by the actual and anticipated consequences of eating.

Previous research has shown that non-human animals exhibit an inverted-U pattern of sweet preference, with consumption increasing across moderate levels of sweetness and then declining for high levels of sweetness. In rodents, this pattern reflects an avoidance of the postingestive effects of consuming energy-dense sugar solutions (conditioned satiation). Here, we examined whether humans also adjust their preferences to compensate for the anticipated energy content/satiating outcomes of consuming sweetened foods. In two experiments (each N = 40), participants were asked to taste and imagine eating small (15 g) and large (250 g) portions of five novel desserts that varied in sweetness. Participants evaluated the desserts' expected satiety, expected satiation, and expected sickliness. A measure of estimated energy content was also derived using a computerized energy compensation test. This procedure was completed before and after consuming a standard lunch. Across both experiments, results confirmed that participants preferred a less sweet dessert when asked to imagine eating a large versus a small portion, and when rating the dessert in a fed versus fasted state. We also obtained evidence that participants anticipated more energy from the sweeter desserts (even in Experiment 2 when half of the participants were informed that the desserts were equated for energy content). However we found only partial evidence for anticipated satiation-expected sickliness was related systematically to increases in sweetness, but expected satiation and expected satiety were only weakly influenced. These findings raise questions about the role of sweetness in the control of food intake (in humans) and the degree to which 'sweet-calorie learning' occurs in complex dietary environments where sweetness may actually be a poor predictor of the energy content of foods.

Large Portions Encourage the Selection of Palatable Rather Than Filling Foods.

BACKGROUND: Portion size is an important driver of larger meals. However, effects on food choice remain unclear. OBJECTIVE: Our aim was to identify how portion size influences the effect of palatability and expected satiety on choice. METHODS: In Study 1, adult participants (n = 24, 87.5% women) evaluated the palatability and expected satiety of 5 lunchtime meals and ranked them in order of preference. Separate ranks were elicited for equicaloric portions from 100 to 800 kcal (100-kcal steps). In Study 2, adult participants (n = 24, 75% women) evaluated 9 meals and ranked 100-600 kcal portions in 3 contexts (scenarios), believing that 1) the next meal would be at 1900, 2) they would receive only a bite of one food, and 3) a favorite dish would be offered immediately afterwards. Regression analysis was used to quantify predictors of choice. RESULTS: In Study 1, the extent to which expected satiety and palatability predicted choice was highly dependent on portion size (P < 0.001). With smaller portions, expected satiety was a positive predictor, playing a role equal to palatability (100-kcal portions: expected satiety, ß: 0.42; palatability, ß: 0.46). With larger portions, palatability was a strong predictor (600-kcal portions: ß: 0.53), and expected satiety was a poor or negative predictor (600-kcal portions: ß: -0.42). In Study 2, this pattern was moderated by context (P = 0.024). Results from scenario 1 replicated Study 1. However, expected satiety was a poor predictor in both scenario 2 (expected satiety was irrelevant) and scenario 3 (satiety was guaranteed), and palatability was the primary driver of choice across all portions. CONCLUSIONS: In adults, expected satiety influences food choice, but only when small equicaloric portions are compared. Larger portions not only promote the consumption of larger meals, but they encourage the adoption of food choice strategies motivated solely by palatability.

Why can't we control our food intake? The downside of dietary variety on learned satiety responses.

A striking feature of the modern food environment is the sheer amount of dietary choice available to the individual. In addition to an endless variety of highly palatable and energy dense foods, efforts to combat obesity have resulted in the production of several low- and reduced-calorie versions of these foods that are marketed to consumers. As a result, we are now confronted with a staggering amount of 'dietary variability'-the same food item can be obtained in a variety of different energy densities. This is a concern because evidence in rodents suggests that this kind of dietary variability can compromise one of the major cognitive determinants of food intake among non-human animals-flavor-nutrient satiety learning. Flavor-nutrient satiety learning enables animals to learn about the energy content or satiating quality of the foods they consume and adjust their intake to fit their energy needs. Notably, evidence suggests that dietary variability can disrupt this kind of learning, leading to overeating and weight gain. Here, I discuss the utility of flavor-nutrient satiety learning in human dietary behavior, highlighting certain features of the modern environment that can be disruptive to the acquisition of this kind of learning in humans. Special emphasis is placed on dietary variability, however I also highlight other aspects of the environment that can undermine this kind of learning, such as competition from other satiety-relevant cues (i.e., food labels), detrimental effects of Western diets on food-related cognitive processing, and the abundance of macronutrients that are inadequate at supporting learned satiety responses. The goal of this work is to highlight novel ways in which the environment may disrupt food-relevant learning and energy intake, and to provide some explanation for the elusive nature of flavor-nutrient learning in humans.

Effects of eating rate on satiety: A role for episodic memory?

Eating slowly is associated with a lower body mass index. However, the underlying mechanism is poorly understood. Here, our objective was to determine whether eating a meal at a slow rate improves episodic memory for the meal and promotes satiety. Participants (N=40) consumed a 400ml portion of tomato soup at either a fast (1.97ml/s) or a slow (0.50ml/s) rate. Appetite ratings were elicited at baseline and at the end of the meal (satiation). Satiety was assessed using; i) an ad libitum biscuit 'taste test' (3h after the meal) and ii) appetite ratings (collected 2h after the meal and after the ad libitum snack). Finally, to evaluate episodic memory for the meal, participants self-served the volume of soup that they believed they had consumed earlier (portion size memory) and completed a rating of memory 'vividness'. Participants who consumed the soup slowly reported a greater increase in fullness, both at the end of the meal and during the inter-meal interval. However, we found little effect of eating rate on subsequent ad libitum snack intake. Importantly, after 3h, participants who ate the soup slowly remembered eating a larger portion. These findings show that eating slowly promotes self-reported satiation and satiety. For the first time, they also suggest that eating rate influences portion size memory. However, eating slowly did not affect ratings of memory vividness and we found little evidence for a relationship between episodic memory and satiety. Therefore, we are unable to conclude that episodic memory mediates effects of eating rate on satiety.

Energy-dense snacks can have the same expected satiation as sugar-containing beverages.

Sugar-sweetened beverages (SSBs) are thought to be problematic for weight management because energy delivered in liquid form may be less effective at suppressing appetite than solid foods. However, little is known about the relative 'expected satiation' (anticipated fullness) of SSBs and solid foods. This is relevant because expected satiation is an important determinant of portion selection and energy intake. Here, we used a method of constant stimuli to assess the expected satiation of test meals that were presented in combination with different caloric and non-caloric beverages (500 ml) (Experiment 1 and 2), as well as with high-energy solid snack foods (Experiment 2). All energy-containing beverages and snack foods were presented in 210 kcal portions. Both experiments found that expected satiation was greater for meals containing caloric versus non-caloric beverages (201.3 ± 17.3 vs. 185.4 ± 14.1 kcal in Experiment 2; p < 0.05). Further, Experiment 2 showed that this difference was greater in participants who were familiar with our test beverages, indicating a role for learning. Notably, we failed to observe a significant difference in expected satiation between any of the caloric beverages and snack foods in Experiment 2 (range: 192.5-205.2 kcal; p = 0.87). This finding suggests that it may be more appropriate to consider beverages and solid foods on the same continuum, recognizing that the expected satiation of some solid foods is as weak as some beverages.

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism.

Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients.

Western-style diet impairs stimulus control by food deprivation state cues: Implications for obesogenic environments.

In western and westernized societies, large portions of the population live in what are considered to be "obesogenic" environments. Among other things, obesogenic environments are characterized by a high prevalence of external cues that are associated with highly palatable, energy-dense foods. One prominent hypothesis suggests that these external cues become such powerful conditioned elicitors of appetitive and eating behavior that they overwhelm the internal, physiological mechanisms that serve to maintain energy balance. The present research investigated a learning mechanism that may underlie this loss of internal relative to external control. In Experiment 1, rats were provided with both auditory cues (external stimuli) and varying levels of food deprivation (internal stimuli) that they could use to solve a simple discrimination task. Despite having access to clearly discriminable external cues, we found that the deprivation cues gained substantial discriminative control over conditioned responding. Experiment 2 found that, compared to standard chow, maintenance on a "western-style" diet high in saturated fat and sugar weakened discriminative control by food deprivation cues, but did not impair learning when external cues were also trained as relevant discriminative signals for sucrose. Thus, eating a western-style diet contributed to a loss of internal control over appetitive behavior relative to external cues. We discuss how this relative loss of control by food deprivation signals may result from interference with hippocampal-dependent learning and memory processes, forming the basis of a vicious-cycle of excessive intake, body weight gain, and progressive cognitive decline that may begin very early in life.

Obesity: Cognitive impairment and the failure to 'eat right'.

A recent study has found that obese women (but not men) have difficulty inhibiting food-rewarded, but not money-rewarded, appetitive behaviour, suggesting that obesity is associated with cognitive deficits that could selectively promote food intake, perhaps in a sex-dependent manner.