An aerobic exercise intervention to improve metabolic health among people living with HIV with at-risk alcohol use: the ALIVE-Ex research study protocol.

BACKGROUND: Effective antiretroviral therapy (ART) in people living with HIV (PLWH) has improved life expectancy and increased risk of age-associated cardiometabolic comorbidities. At-risk alcohol use is more frequent among PLWH and increases the risk of health challenges. PLWH with at-risk alcohol use are more likely to meet criteria for prediabetes/diabetes and this is associated with impaired whole-body glucose-insulin dynamics. METHODS: The Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions Study (ALIVE-Ex Study, NCT03299205) is a longitudinal, prospective, interventional study to determine the effects of an aerobic exercise protocol on improving dysglycemia among PLWH with at-risk alcohol use. The intervention is a moderate intensity aerobic exercise protocol implemented 3 days per week for 10 weeks at the Louisiana State University Health Sciences Center-New Orleans. Participants who have a fasting blood glucose level between 94 and 125 mg/dl will be enrolled in the study. Oral glucose tolerance tests, fitness assessments, and skeletal muscle biopsies will be performed pre- and post-exercise intervention. The primary outcome is to determine whether the exercise protocol improves measures of whole-body glucose-insulin dynamics, cardiorespiratory fitness, and skeletal muscle metabolic and bioenergetic function. Secondary outcomes are to determine whether the exercise intervention improves cognitive function and overall quality of life. Results generated will demonstrate the effect of exercise on glycemic measures in PLWH with subclinical dysglycemia and at-risk alcohol use. CONCLUSIONS: The proposed intervention will also have the potential to be scalable to promote lifestyle changes among PLWH, particularly in underserved communities.

Orlistat mouth rinse: Using the tongue to deliver antiobesity medication in a double-blind randomized crossover pilot trial.

AIM: To investigate the effects of an orlistat mouth rinse on the intake of a high-fat meal. METHODS: A double-blind, balanced order, crossover study was conducted in participants (n = 10, body mass index 25-30 kg/m2 ) assigned to receive placebo or orlistat (24 mg/mL) prior to a high-fat meal. Participants were divided into low- or high-fat consumers based on calories consumed from fat following placebo administration. RESULTS: The orlistat mouth rinse decreased total and fat calories consumed during the high-fat meal in high-fat consumers, and did not alter calories consumed in low-fat consumers (P < 0.05). CONCLUSIONS: Orlistat decreases long-chain fatty acid (LCFA) absorption by inhibiting lipases that breakdown triglycerides. Orlistat mouth rinse decreased fat intake in high-fat consumers, suggesting that orlistat inhibited the detection of LCFAs from the high-fat test meal. Lingual delivery of orlistat is predicted to eliminate the risk of oil incontinence and promote weight loss in individuals who prefer fat.

The hypothalamic neuropeptide, QRFP, regulates high fat diet intake in female Long-Evans rats following ovariectomy.

Obesity rates in women continue to increase throughout the lifespan and obesity-related comorbidities are prevalent in women in estrogen deficiency. The hypothalamic neuropeptide, QRFP, is an orexigenic peptide that increases the intake of high fat diet (HFD) in female rats and is overexpressed following ovariectomy (OVX). Therefore, the goal of the current series of experiments was to elucidate the effect of QRFP on HFD intake following OVX and determine if QRFP-26 administration in ovariectomized females altered expression of prepro-neuropeptide Y (NPY), agouti-related peptide (AgRP) and proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus (MBH) and prepro-orexin in the lateral hypothalamus (LH). The intake of HFD was measured following acute administration of QRFP-26 prior to or following estradiol benzoate (EB) treatment in ovariectomized females. When administered prior to EB treatment, QRFP-26 increased HFD intake. EB treatment attenuated the effects of QRFP-26 on HFD intake. Sub-chronic, continuous administration of QRFP-26 increased HFD intake and weight gain following OVX. Subchronic, continuous administration of QRFP siRNA into the 3rd ventricle via osmotic pump decreased prepro-QRFP mRNA levels in the MBH by ∼75%, decreased HFD intake and decreased weight gain following OVX. QRFP-26administration did not alter the expression of prepro-NPY, AgRP or POMC mRNA in the MBH, but decreased prepro-orexin mRNA in the LH of ovariectomized females. Overall, results from these studies support the orexigenic neuropeptide, QRFP, as an important mediator of the ingestion of highly palatable foods and subsequent weight gain in females during estrogen deficiency.

Unique circulating microRNA associations with dysglycemia in people living with HIV and alcohol use.

People living with HIV (PLWH) have increased prevalence of comorbid conditions including insulin resistance and at-risk alcohol use. Circulating microRNAs (miRs) may serve as minimally invasive indicators of pathophysiological states. We aimed to identify whether alcohol modulates circulating miR associations with measures of glucose/insulin dynamics in PLWH. PLWH (n = 96; 69.8% males) enrolled in the Alcohol & Metabolic Comorbidities in PLWH: Evidence-Driven Interventions (ALIVE-Ex) study were stratified into negative phosphatidylethanol (PEth < 8 ng/mL, n = 42) and positive PEth (PEth ≥ 8 ng/mL, n = 54) groups. An oral glucose tolerance test (OGTT) was administered, and total RNA was isolated from fasting plasma to determine absolute miR expression. Circulating miRs were selected based on their role in skeletal muscle (miR-133a and miR-206), pancreatic ß-cell (miR-375), liver (miR-20a), and adipose tissue (miR-let-7b, miR-146a, and miR-221) function. Correlation and multiple regression analyses between miR expression and adiponectin, 2 h glucose, insulin, and C-peptide values were performed adjusting for body mass index (BMI) category, age, sex, and viral load. miR-133a was negatively associated with adiponectin (P = 0.002) in the negative PEth group, and miR-20a was positively associated with 2 h glucose (P = 0.013) in the positive PEth group. Regression analyses combining miRs demonstrated that miR-133a (P < 0.001) and miR-221 (P = 0.010) together predicted adiponectin in the negative PEth group. miR-20a (P < 0.001) and miR-375 (P = 0.002) together predicted 2 h glucose in the positive PEth group. Our results indicate that associations between miRs and measures of glucose/insulin dynamics differed between PEth groups, suggesting that the pathophysiological mechanisms contributing to altered glucose homeostasis in PLWH are potentially modulated by alcohol use.

Associations of Binge Drinking and Heavy Alcohol Use on Sugar and Fat Intake in a Cohort of Southern People Living with HIV.

AIMS: To assess whether binge drinking and heavy alcohol use are associated with increased sugar and fat consumption among a Southern cohort of people living with HIV (PWH). METHODS: This was a cross-sectional analysis of PWH enrolled in the New Orleans Alcohol use in HIV (NOAH) Study (n = 215). Binge and heavy drinking were identified through a 30-day Alcohol Timeline-Followback and dietary intake was assessed through a 24-hour dietary recall. RESULTS: Participants were 65.4% male, 83.3% Black, with a mean age of 49.2 ± 9.9. Heavy drinkers consumed more total calories than abstainers (P = 0.035) and low-to-moderate drinkers (P = 0.024), and binge drinkers consumed more calories than non-binge drinkers (P = 0.025). Binge and heavy drinkers had significantly higher intake of total and saturated fat in grams. However, substantially increased caloric intake among these participants led to non-significant associations for alcohol use with high total and saturated fat intake as a percent of total energy intake (%TEI). Binge drinkers had lower odds of consuming high sugar as a %TEI (odds ratio: 0.31 [0.14, 0.68]). Additionally, sugar intake predicted total and saturated fat intake, and this association was slightly higher among binge drinkers (total fat P-value: 0.12). CONCLUSIONS: In this population of PWH, while binge and heavy drinking predicted higher caloric and fat intake in grams, binge drinkers were less likely to consume a high-sugar diet. This analysis suggests that interventions focused on reduced alcohol use may be especially beneficial in reducing metabolic disease burden in PWH if supplemented with information on incorporating lower energy-dense foods with reduced fat.

Skeletal muscle bioenergetic health and function in people living with HIV: association with glucose tolerance and alcohol use.

At-risk alcohol use is prevalent and increases dysglycemia among people living with human immunodeficiency virus (PLWH). Skeletal muscle (SKM) bioenergetic dysregulation is implicated in dysglycemia and type 2 diabetes. The objective of this study was to determine the relationship between at-risk alcohol, glucose tolerance, and SKM bioenergetic function in PLWH. Thirty-five PLWH (11 females, 24 males, age: 53 ± 9 yr, body mass index: 29.0 ± 6.6 kg/m2) with elevated fasting glucose enrolled in the ALIVE-Ex study provided medical history and alcohol use information [Alcohol Use Disorders Identification Test (AUDIT)], then underwent an oral glucose tolerance test (OGTT) and SKM biopsy. Bioenergetic health and function and mitochondrial volume were measured in isolated myoblasts. Mitochondrial gene expression was measured in SKM. Linear regression adjusting for age, sex, and smoking was performed to examine the relationship between glucose tolerance (2-h glucose post-OGTT), AUDIT, and their interaction with each outcome measure. Negative indicators of bioenergetic health were significantly (P < 0.05) greater with higher 2-h glucose (proton leak) and AUDIT (proton leak, nonmitochondrial oxygen consumption, and bioenergetic health index). Mitochondrial volume was increased with the interaction of higher 2-h glucose and AUDIT. Mitochondrial gene expression decreased with higher 2-h glucose (TFAM, PGC1B, PPARG, MFN1), AUDIT (MFN1, DRP1, MFF), and their interaction (PPARG, PPARD, MFF). Decreased expression of mitochondrial genes were coupled with increased mitochondrial volume and decreased bioenergetic health in SKM of PLWH with higher AUDIT and 2-h glucose. We hypothesize these mechanisms reflect poorer mitochondrial health and may precede overt SKM bioenergetic dysregulation observed in type 2 diabetes.

Alcohol use and dysglycemia among people living with human immunodeficiency virus (HIV) in the Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions (ALIVE-Ex) study.

BACKGROUND: At-risk alcohol use is a common and costly form of substance misuse that is highly prevalent among people living with HIV (PLWH). The goal of the current analysis was to test the hypothesis that PLWH with at-risk alcohol use are more likely to meet the clinical criteria for prediabetes/diabetes than PLWH with low-risk alcohol use. METHODS: A cross-sectional analysis was performed on measures of alcohol and glycemic control in adult PLWH (n = 105) enrolled in a prospective, interventional study (the ALIVE-Ex Study (NCT03299205)) that investigated the effects of aerobic exercise on metabolic dysregulation in PLWH with at-risk alcohol use. The Alcohol Use Disorders Identification Test (AUDIT), Timeline Followback, and phosphatidylethanol (PEth) level were used to measure alcohol use. Participants were stratified into low-risk (AUDIT score < 5) and at-risk alcohol use (AUDIT  score ≥ 5). All participants underwent an oral glucose tolerance test and measures of glycemic control- the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Matsuda Index - were correlated with alcohol measures and compared by AUDIT score group using mixed-effects linear and logistic regression models, adjusting for age, sex, race, body mass index (BMI), and viral load. RESULTS: In response to the glucose challenge, participants with at-risk alcohol use (n = 46) had higher glucose levels and were five times more likely to meet criteria for prediabetes/diabetes (OR: 5.3 (1.8, 15.9)) than participants with an AUDIT score < 5. Two-hour glucose values were positively associated with AUDIT score and PEth level and a higher percentage of PLWH with at-risk alcohol use had glucose values ≥140 mg/dl than those with low-risk alcohol use (34.8% vs. 10.2%, respectively). CONCLUSION: In this cohort of PLWH, at-risk alcohol use increased the likelihood of meeting the clinical criteria for prediabetes/diabetes (2-h glucose level ≥140 mg/dl). Established determinants of metabolic dysfunction (e.g., BMI, waist-hip ratio) were not associated with greater alcohol use and dysglycemia, suggesting that other mechanisms may contribute to the impaired glycemic control observed in this cohort.

Sex differences in markers of metabolic syndrome and adipose tissue inflammation in obesity-prone, Osborne-Mendel and obesity-resistant, S5B/Pl rats.

The current study examined the role of sex differences in the development of risk factors associated with obesity and its comorbidities using models that differ in their susceptibility to develop obesity, obesity-resistant S5B/Pl (S5B) and obesity-prone Osborne-Mendel (OM) rats. Male and female rats were fed a low fat or high fat diet (HFD) and markers of metabolic syndrome (MetSyn) and expression of inflammatory cytokines/chemokines in visceral and subcutaneous adipose depots were measured. We hypothesized that male and female OM and S5B rats would exhibit differential responses to the consumption of HFD and that females, regardless of susceptibility to develop obesity, would display decreased obesity-related risk factors. Results suggested that consumption of HFD increased adiposity and fasting glucose levels in male OM and S5B rats, decreased circulating adiponectin levels in male S5B rats, and increased body weight and triglyceride levels in male OM rats. The consumption of HFD increased body weight and adiposity in female OM rats, not female S5B rats. Overall, female rats did not meet criteria for MetSyn, while male rats consuming HFD met criteria for MetSyn. Visceral and subcutaneous adipose tissue inflammation was higher in male rats. In visceral adipose tissue, HFD consumption differentially altered expression of cytokines in male and female S5B and OM rats. These findings suggest that resistance to obesity in males may be overridden by chronic consumption of HFD and lead to increased risk for development of obesity-related comorbidities, while female rats appear to be protected from the adverse effects of HFD consumption.

Transection of Gustatory Nerves Differentially Affects Dietary Fat Intake in Obesity-Prone and Obesity-Resistant Rats.

The current prevalence of obesity has been linked to the consumption of highly palatable foods and may be mediated by a dysregulated or hyposensitive orosensory perception of dietary fat, thereby contributing to the susceptibility to develop obesity. The goal of the current study was to investigate the role of lingual taste input in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats on the consumption of a high-fat diet (HFD). Density of fungiform papillae was assessed as a marker of general orosensory input. To determine if orosensory afferent input mediates dietary fat intake, surgical transection of the chorda tympani and glossopharyngeal nerves (GLX/CTX) was performed in OP and OR rats and HFD caloric intake and body weight were measured. Fungiform papillae density was lower in OP rats, compared with OR rats. GLX/CTX decreased orosensory input in both OP and OR rats, as measured by an increase in the intake of a bitter, quinine solution. Consumption of low-fat diet was not altered by GLX/CTX in OP and OR rats; however, GLX/CTX decreased HFD intake in OR, without altering HFD intake in OP rats. Overall, these data suggest that inhibition of orosensory input in OP rats do not decrease fat intake, thereby supporting that idea that hyposensitive and/or dysregulated orosensory perception of highly palatable foods contribute to the susceptibility to develop obesity.

Prevalence of Insulin Resistance in Adults Living with HIV: Implications of Alcohol Use.

Unhealthy alcohol use is prevalent among persons living with HIV (PLWH). Aging and increased survival of PLWH on antiretroviral therapy (ART) are complicated by metabolic dysregulation and increased risk of insulin resistance (IR) and diabetes mellitus. The objective of this study was to determine the prevalence and association of IR with unhealthy alcohol use in adult in-care PLWH. A cross-sectional analysis of metabolic parameters and alcohol use characteristics was conducted in adult PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) Study. IR was estimated using homeostatic model assessment (HOMA-IR), triglyceride index, and McAuley index and beta cell function (HOMA-ß). Alcohol use was assessed using Alcohol Use Disorders Identification Test (AUDIT)-C, 30-day timeline followback (TLFB), lifetime drinking history, and phosphatidylethanol (PEth) measures. A total of 351 participants, with a mean age [±standard deviation (SD)] of 48.1 ± 10.4 years, were included (69.6% male). Of these, 57% had an AUDIT-C score of 4 or greater, indicating unhealthy alcohol use. Mean body mass index (BMI) was 27.2 ± 7.0 kg/m2, 36.4% met criteria for metabolic syndrome, and 14% were diagnosed with diabetes. After adjusting for education, race, BMI, smoking status, viral load, CD4 count, use of protease inhibitors, statins, or metformin; physical activity and diabetes diagnosis, HOMA-IR, and McAuley index were negatively associated with AUDIT-C, and HOMA-ß cell function was negatively associated with AUDIT-C, PEth, and TLFB. Cross-sectional analysis of NOAH participants indicates that alcohol use is associated with decreased HOMA-ß cell function, suggesting dysregulation of endocrine pancreatic function.

Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity.

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.

Expression of neural markers of gustatory signaling are differentially altered by continuous and intermittent feeding patterns.

Food intake patterns are regulated by signals from the gustatory neural circuit, a complex neural network that begins at the tongue and continues to homeostatic and hedonic brain regions involved in eating behavior. The goal of the current study was to investigate the short-term effects of continuous access to a high fat diet (HFD) versus limited access to dietary fat on the gustatory neural circuit. Male Sprague-Dawley rats were fed a chow diet, a HFD (56% kcal from fat), or provided limited, daily (2 h/day) or limited, intermittent (2 h/day, 3 times/week) access to vegetable shortening for 2 weeks. Real time PCR was used to determine mRNA expression of markers of fat sensing/signaling (e.g. CD36) on the circumvallate papillae, markers of homeostatic eating in the mediobasal hypothalamus (MBH) and markers of hedonic eating in the nucleus accumbens (NAc). Continuous HFD increased mRNA levels of lingual CD36 and serotonin signaling, altered markers of homeostatic and hedonic eating. Limited, intermittent access to dietary fat selectively altered the expression of genes associated with the regulation of dopamine signaling. Overall, these data suggest that short-term, continuous access to HFD leads to altered fat taste and decreased expression of markers of homeostatic and hedonic eating. Limited, intermittent access, or binge-like, consumption of dietary fat led to an overall increase in markers of hedonic eating, without altering expression of lingual fat sensors or homeostatic eating. These data suggest that there are differential effects of meal patterns on gustatory neurocircuitry which may regulate the overconsumption of fat and lead to obesity.

The prevalence of cardio-metabolic risk factors is differentially elevated in obesity-prone Osborne-Mendel and obesity-resistant S5B/Pl rats.

AIMS: Individual susceptibility to develop obesity may impact the development of cardio-metabolic risk factors that lead to obesity-related comorbid conditions. Obesity-prone Osborne-Mendel (OM) rats expressed higher levels of visceral adipose inflammation than obesity-resistant, S5B/Pl (S5B) rats. However, the consumption of a high fat diet (HFD) differentially affected OM and S5B rats and induced an increase in visceral adipose inflammation in S5B rats. The current study examined the effects of HFD consumption on cardio-metabolic risk factors in OM and S5B rats. MATERIALS & METHODS: Glucose regulation and circulating levels of lipids, adiponectin and C-reactive protein were assessed following 8 weeks of HFD or low fat diet (LFD) consumption. Left ventricle hypertrophy and mRNA expression of cardiovascular disease biomarkers were also quantified in OM and S5B rats. KEY FINDINGS: Circulating levels of triglycerides were higher, while HDL cholesterol, adiponectin and glycemic control were lower in OM rats, compared to S5B rats. In the left ventricle, BNP and CTGF mRNA expression were higher in OM rats and IL-6, IL-1ß, VEGF, and iNOS mRNA expression were higher in S5B rats. SIGNIFICANCE: These findings support the hypothesis that cardio-metabolic risk factors are increased in obesity-prone individuals, which may increase the risk for the development of obesity-related comorbidities. In the current models, obesity-resistant S5B rats also exhibited cardiovascular risk factors supporting the importance of monitoring cardiovascular health in individuals characterized as obesity-resistant.

Lingual CD36 and nutritional status differentially regulate fat preference in obesity-prone and obesity-resistant rats.

Lingual fatty acid receptors (i.e. CD36) mediate the orosensory perception of fat/fatty acids and may contribute to the susceptibility to develop obesity. The current study tested the hypothesis that fat/fatty acid preference in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats is mediated by nutritional status and lingual CD36. To determine if nutritional status affected linoleic acid (LA) preference in OP and OR rats, rats were either fasted overnight or fed a high fat diet (60% kcal from fat). In OR rats, fasting increased the preference for higher concentrations of LA (1.0%), while consumption of a high fat diet decreased LA preference. In OP rats, fasting increased the preference for lower concentrations of LA (0.25%), however high fat diet consumption did not alter LA preference. To determine if lingual CD36 mediated the effects of an overnight fast on LA preference, the expression of lingual CD36 mRNA was assessed and the effect of lingual application of CD36 siRNA on LA preference was determined. Fasting increased lingual CD36 mRNA expression in OR rats, but failed to alter lingual CD36 mRNA in OP rats. Following an overnight fast, application of lingual CD36 siRNA led to a decrease in LA preference in OR, but not OP rats. Lingual application of CD36 siRNA was also used to determine if lingual CD36 mediated the intake and preference for a high fat diet in OP and OR rats. CD36 siRNA decreased the preference and intake of high fat diet in OR rats, but not OP rats. The results from this study suggest that the dysregulation of lingual CD36 in OP rats is a potential factor leading to increased fat intake and fat preference and an enhanced susceptibility to develop obesity.

Recent advances in the modification of taste and food preferences following bariatric surgery.

There is a large body of evidence indicating that bariatric surgery provides durable weight loss and health benefits to patients who are obese and have comorbidities such as type 2 diabetes (T2D). However, there are still many questions related to mechanisms of metabolic improvement, predictors of success/failure, and long term consequences, which need to be answered. More recently, there has been a particular interest in the modulation of taste and food preferences that occurs after bariatric surgery and how this affects weight loss in different individuals. Animal models as well as human studies have shed some light on the role of taste in changing food preferences and how these changes may affect weight loss after surgery. The goal of this review is to discuss the physiological and behavioral consequences of bariatric surgery as a treatment for obesity and T2D, with particular emphasis on recent studies describing bariatric surgery-induced modifications in taste perception and food preferences.

The effects of high fat diet and estradiol on hypothalamic prepro-QRFP mRNA expression in female rats.

Estradiol (E2) is a potent regulator of feeding behavior, body weight and adiposity in females. The hypothalamic neuropeptide, QRFP, is an orexigenic peptide that increases the consumption of high fat diet (HFD) in intact female rats. Therefore, the goal of the current series of studies was to elucidate the effects of E2 on the expression of hypothalamic QRFP and its receptors, QRFP-r1 and QRFP-r2, in female rats fed a HFD. Alterations in prepro-QRFP, QRFP-r1, and QRFP-r2 expression across the estrous cycle, following ovariectomy (OVX) and following estradiol benzoate (EB) treatment were assessed in the ventral medial nucleus of the hypothalamus/arcuate nucleus (VMH/ARC) and the lateral hypothalamus. In intact females, consumption of HFD increased prepro-QRFP and QRFP-r1 mRNA levels in the VMH/ARC during diestrus, a phase associated with increased food intake and low levels of E2. To assess the effects of diminished endogenous E2, rats were ovariectomized. HFD consumption and OVX increased prepro-QRFP mRNA in the VMH/ARC. Ovariectomized rats consuming HFD expressed the highest levels of QRFP. In the third experiment, all rats received EB replacement every 4days following OVX to examine the effects of E2 on QRFP expression. Prepro-QRFP, QRFP-r1 and QRFP-r2 mRNA were assessed prior to and following EB administration. EB replacement significantly reduced prepro-QRFP mRNA expression in the VMH/ARC. Overall these studies support a role for E2 in the regulation of prepro-QRFP mRNA in the VMH/ARC and suggest that E2's effects on food intake may be via a direct effect on the orexigenic peptide, QRFP.

High-fat diet differentially regulates metabolic parameters in obesity-resistant S5B/Pl rats and obesity-prone Osborne-Mendel rats.

The current experiment tested the hypothesis that consumption of a high-fat diet (HFD) would differentially affect metabolic parameters in obesity-prone Osborne-Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. In OM rats consuming a HFD, an increase in HFD intake, body mass, and percent fat mass, and a HFD-induced decrease in metabolic rate and energy expenditure were demonstrated. In S5B rats consuming a HFD, no change in percent body fat or HFD intake was demonstrated and HFD increased metabolic rate and energy expenditure. To assess whether HFD differentially altered skeletal muscle markers of metabolism in OM and S5B rats, the expression of the transporters, CD36 and GLUT4, and the energy sensors, AMPK and PPARγ, in the gastrocnemius muscle was measured. Oxidation and lipid accumulation in the gastrocnemius muscle was histologically determined. Consumption of a HFD decreased phosphorylated AMPK and PPARγ expression in the skeletal muscle of obesity-prone OM rats. Lipid accumulation in skeletal muscle was significantly higher in OM rats fed a HFD. Overall, these data suggest that the differential response to HFD on metabolic rate, energy expenditure, and phosphorylated AMPK and PPARγ in OM and S5B rats, may partially account for differences in the susceptibility to develop obesity.

Differences in short-term food preferences following vertical sleeve gastrectomy and Roux-en-Y gastric bypass surgery.

Bariatric surgery is effective in reducing body weight and obesity-related comorbidities. This study examined differences in the short-term effect of Roux en Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on the hedonic rating of food. Predominantly black women with complicated obesity and a BMI>50 g/m(2) completed a validated food preference questionnaire before and 1-3 months following surgery. Analysis of preference scores indicated that the preference for fat decreased with both surgeries. VSG also decreased the preference for sugar. Further studies are needed to evaluate long term effects of surgery on food preferences and to elucidate physiological mechanisms.

The effect of caffeine and albuterol on body composition and metabolic rate.

OBJECTIVE: Caffeine and ephedrine was an effective combination therapy for weight loss until ephedrine was removed from the market due to safety concerns. This study investigated the combination of caffeine and albuterol as a possibly safer alternative to ephedrine. METHODS: In a series of experiments using cultured adipocytes, rat models, and humans, the effects of caffeine and albuterol on lipolysis, metabolic rate, food intake, and body composition were evaluated. RESULTS: Both caffeine and albuterol enhanced lipolysis in cultured adipocytes. Acute treatment of humans with caffeine and/or albuterol increased resting metabolic rate. Longer-term studies of rats revealed a trend for increased metabolic rate with albuterol treatment. There was increased lean mass gain concurrent with decreased fat mass gain with caffeine/albuterol treatment that was greater than albuterol treatment alone. CONCLUSIONS: In rats, albuterol with caffeine produced significantly greater increases in lean body mass and reductions in fat mass without changes in food intake after 4-8 weeks of treatment. Since caffeine and albuterol are approved for the treatment of asthma in children and adolescents at the doses tested and change body composition without changing food intake, this combination may deserve further exploration for use in treating pediatric obesity.

QRFP-26 enhances insulin's effects on glucose uptake in rat skeletal muscle cells.

QRFP is expressed in central and peripheral regions important for nutrient intake and metabolism. Central administration of QRFP-26 and QRFP-43 induces a macronutrient specific increase in the intake of high fat diet in male and female rats. Recently, cell culture models have indicated that QRFP-26 and QRFP-43 are involved in glucose and fatty acid uptake in pancreatic islets and adipocytes. Since skeletal muscle is a major consumer of circulating glucose and a primary contributor to whole body metabolism, the current study examined the effects of QRFP-26 and QRFP-43 on insulin-stimulated uptake of glucose in skeletal muscle using L6 myotubes. The current experiments were designed to test the hypothesis that QRFP and its receptors, GPR103a and GPR103b are expressed in L6 myotubes and that QRFP-26 and QRFP-43 affect insulin-stimulated uptake of glucose in L6 myotubes. The results indicate that prepro-QRFP mRNA and GPR103a mRNA are expressed in L6 cells, though GPR103b mRNA was not detected. Using complementary assays, co-incubation with QRFP-26, increased insulin's ability to induce glycogen synthesis and 2-deoxyglucose uptake in L6 cells. These data suggest that QRFP-26, but not QRFP-43, is involved in the metabolic effects of skeletal muscle and may enhance insulin's effects on glucose uptake in skeletal muscle. These data support a role for QRFP as a modulator of nutrient intake in skeletal muscle.