Weight Cycling Research Articles

Weight cycling and risk of clinical adverse events in patients with heart failure with preserved ejection fraction: a post-hoc analysis of TOPCAT.

Previous studies hardly evaluated the association of variability of body mass index (BMI) or waist circumference with clinical adverse events and investigated whether weight cycling had an effect on the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). This study was a post-hoc analysis of TOPCAT. Three outcomes were evaluated: the primary endpoint, cardiovascular disease (CVD) death, and heart failure hospitalization. Among them, CVD death and hospitalization were outcomes of heart failure. Kaplan-Meier curves were used to describe the cumulative risk of outcome and were tested using the log-rank test. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95%CIs for outcomes. We also performed a subgroup analysis, and several subgroups were compared. A total of 3,146 patients were included. In the Kaplan-Meier curves, the coefficients of variation of both BMI and waist circumference were grouped according to quartiles, with the Q4 group having the highest cumulative risk (log-rank P < 0.001). In the coefficient of BMI variation and the outcomes, the HRs for group Q4 of coefficient of variation of BMI were 2.35 (95%CI: 1.82, 3.03) for the primary endpoint, 2.40 (95%CI: 1.69, 3.40) for death, and 2.33 (95%CI: 1.68, 3.22) for HF hospitalization in model 3 (fully adjusted model) compared with group Q1. In the coefficient of waist circumference variation and the outcomes, group Q4 had increased hazard of the primary endpoint [HR: 2.39 (95%CI: 1.84, 3.12)], CVD death [HR: 3.29 (95%CI: 2.28, 4.77)], and HF hospitalization [HR: 1.98 (95%CI 1.43, 2.75)] in model 3 (fully adjusted model) compared with group Q1. In the subgroup analysis, there was a significant interaction in the diabetes mellitus subgroup (P for interaction = 0.0234). Weight cycling had a negative effect on the prognosis of patients with HFpEF. The presence of comorbid diabetes weakened the relationship between waist circumference variability and clinical adverse events.

Weight cycling may induce lipid handling in mast cells

Abstract Weight cycling worsens diabetes risk in both humans and mice. We recently found that weight loss and weight cycling induce many immunological changes in the adipose tissue of mice by single cell RNA-sequencing. We also found a substantial increase in adipose mast cells with weight cycling, but not weight loss. The purpose of this study was to confirm and characterize the changes in mast cells with weight cycling. However, using flow cytometry (cKit+FcER1+) and Toluidine blue staining, we found that adipose mast cells are greatest in the weight loss group, in contrast to our prior study using single cell RNA-sequencing. Upon further analysis, we found two unique mast cell populations in our single cell sequencing dataset: one that we consider traditional mast cells and one with lower expression of mast cell surface and protease genes and elevated expression of lipid handling and antigen presentation genes. The second fraction appeared similar to lipid-associated macrophages and accounted for most of the mast cells in the weight cycled group. By flow cytometry, we confirmed the %CD9+, MHCII (I-A/I-E)+, and CD74+ mast cells were highest in weight cycled mice. We also found two mast cell populations in human subcutaneous adipose tissue that appear similar to the murine populations in our dataset, with one population significantly correlating with weight variability. Together, these data suggest that weight cycling may induce a population of lipid-associated mast cells. We next aim to to induce lipid handling in bone marrow derived mast cells by repeated exposure to adipose conditioned media in order to understand the mechanisms which induce lipid handling. This project was funded by a Veterans Affairs Merit Award 5I01BX002195 to AHH. AHH is also supported by a Career Scientist Award from the Veterans Affairs (IK6 BX005649). HLC was funded by an American Heart Association Postdoctoral Fellowship (20POST35120547), MAC was funded by an NIH F31 Predoctoral Fellowship (1F31DK123881), and both were previously supported by the Molecular Endocrinology Training Program (T32 DK07563). Additionally, the human mast cell work was funded by VICTR grants to HLC and MM. The Vanderbilt Institute for Clinical and Translational Research (VICTR) is funded by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program, Award Number 5UL1TR002243-03.

Characterizing left ventricular diastolic function, exercise capacity and the adrenal cortex after yoyo diet-induced weight-cycling in mice with or without ovariectomy-induced post-menopausal condition

Studies report that only ∼20% of overweight people achieve sustainable weight loss with the risk to incur weight cycling. The over-shoot theory relates to an increased risk to develop metabolic syndrome (metS) and associated cardiovascular dysfunctions with successive phases of weight gain. In women, the prevalence of metS and heart failure with preserved ejection fraction (HFpEF) increases after menopause. To characterize the cardiac and adrenal consequences of yoyo-dieting in female mice with or without ovariectomy-induced post-menopausal condition. After ovariectomy (OVX) or not, mice were subjected to 3 cycles of a 60% high fat diet (HFD, 4-week duration) followed by a standard diet (SD) (increasing duration of 4, 6 and 10 weeks). Non-OVX control mice (CTL) were fed a SD. To assess the development of HFpEF, left ventricular (LV) function was characterized by ultrasound and invasive hemodynamics. Exercise capacity was evaluated on a treadmill. The morphology of the adrenal gland was described using HES staining, Sirius Red and immunofluorescence. Adrenal function and the vascular network were assessed using RT-qPCR to quantify mRNA expression for genes involved respectively in steroidogenesis and angiogenesis. At the end of the protocol, Yoyo mice had incomplete weight recovery and an insulin tolerance test indicated decreased sensitivity to the hormone. Moreover, there was an increase in LV-end-diastolic-pressure-volume-relation in OVX-Yoyo mice compared to CTL mice, indicating decreased compliance. In addition, the absence of difference in systolic fractional shortening (i.e., ejection fraction) and a lower exercise capacity in OVX-Yoyo mice compared to CTL demonstrated HFpEF. These OVX-Yoyo mice had major disorganization and remodeling in the adrenal gland with the apparition of dysplasia and fibrosis throughout the cortex. The vascular architecture was also affected, with lower expression of Vegf-a. Despite higher adrenal weight, there was no difference in cell proliferation. Whereas CYP11B2 expression, coding for the aldosterone synthase was not affected, the mRNA expression of CYP11B1, involved in glucocorticoids biosynthesis, was lower in OVX-Yoyo mice. Female mice in post-menopausal condition and subjected to yoyo-dieting showed an increased risk of developing HFpEF as well as major morphological and functional differences in the adrenal cortex.

Mental Fatigue: The Cost of Cognitive Loading on Weight Lifting, Resistance Training, and Cycling Performance.

Mental fatigue (MF) can impair physical performance in sport. We tested the hypothesis that cognitive load alone, and intermixed with standard resistance training, would induce MF, increase rating of perceived exertion (RPE), alter perception of weight lifting and training, and impair cycling time-trial performance. This 2-part study employed a within-participant design. In part 1, after establishing leg-extension 1-repetition maximum(1RM), 16 participants lifted and briefly held weights at 20%, 40%, 60%, and 80% of 1RM. RPE and electromyography (EMG) were measured for each lift. During the testing sessions, participants completed cognitive tasks (MF condition) or watched neutral videos (control condition) for 90minutes before lifting the weights. In part 2, they completed submaximal resistance training comprising 6 weight training exercises followed by a 20-minute cycling time trial. In the MF condition, they completed cognitive tasks before and between weight training exercises. In the control condition, they watched neutral videos. Mood (Brunel Mood Scale), workload (National Aeronautics and Space Administration Task Load Index), MF-visual analogue scale (MF-VAS), RPE, psychomotor vigilance, distance cycled, power output, heart rate, and blood lactate were measured. In part 1, the cognitive task increased lift-induced RPE (P = .011), increased MF-VAS (P = .002), and altered mood (P < .001) compared with control. EMG did not differ between conditions. In part 2, the cognitive tasks increased RPE (P < .001), MF-VAS (P < .001), and mental workload (P < .001), but reduced cycling time-trial power (P = .032) and distance (P = .023) compared with control. Heart rate and blood lactate did not differ between conditions. A state of MF induced by cognitive load, alone or intermixed with physical load, increased RPE during weight lifting and training and impaired subsequent cycling performance.

Weight cycling among Indonesian college students in West Java province during the COVID-19 pandemic

Introduction: Changes in our bodies can cause several problems, particularly for students who are concerned about maintaining an ideal body shape. Many of them try to diet, but their body returns to its previous weight or even increases in weight. Thus, this study aimed to determine the factors that influence the incidence of weight cycling in Indonesian students during the COVID-19 pandemic. Methods: This cross-sectional study used purposive sampling to collect data. Three hundred college students from West Java province, Indonesia, participated. Weight cycling was the dependent variable and the independent variables were physical activity, sex, and weight management. Multivariate logistic regression analysis was used to determine the factors influencing the incidence of weight cycling. Results: Sex, physical activity, skipping meals, and snacking were determinants related to weight cycling incidence. Females had a 0.7 times higher risk of experiencing weight cycling than males. Inactive students were 4.7 times more likely to become weight cyclers, and those who rarely skipped mealtime had lower risk of being weight cyclers. Students who sometimes and always consumed snacks had higher risk of becoming weight cyclers by 3.3 and 2.7 times, respectively, compared to those who rarely consumed snacks. Conclusion: Regular physical activity, not skipping meals, especially breakfast, and practising a healthy diet every day are recommended strategies to avoid weight cycling during a pandemic.

Weight variability and diabetes complications

Body weight is a recognized risk factor for cardiovascular diseases (CVD). More recently, weight variability, i.e. the oscillation of body weight over time, has also been suggested to be independently associated with development of CVD and mortality in subjects without diabetes and in people with both type 1 and type 2 diabetes (T2D). In T2D, weight variability emerged as one of the most relevant risk factors for CVD and it was suggested to interact with the variability of other risk factors to identify people at high cardiovascular risk. In addition, weight variability seems also to confer a higher risk for microvascular complications in people with T2D. While the exact mechanism linking weight variability to CVD is unknown, evidence from experimental models suggests that weight cycling promote an enduring pro-inflammatory program in the adipose tissue. Here we review the clinical evidence relative to the association of weight variability with CVD and microvascular complications of diabetes. We then briefly summarize the alterations proposed to explain this association. Finally, we synthesize the possible strategies, e.g. specific dietetic regimens and available glucose-lowering drugs, to minimize weight fluctuations.

You are what you eat? Rodent study suggests defended body weight mainly dictated by fatcontent of diet.

Preclinical and clinical data suggest that body weight (i.e., body fat) is physiologically regulated, and the high heritability seen from monozygotic twin studies suggests a genetic basis to one's defended body weight. Genome-wide association studies have found that a high proportion of variants that correlate with elevated body mass index are expressed in the central nervous system, signifying that the molecular predicates that likely encode for defended body weight will be found in the brain [(1)]. In this context, an individual integrates peripheral signals (e.g., adipokines, myokines, hepatokines) relaying the metabolic state of various tissues to the brain and reacts to maintain relatively stable weight. However, the recent increased prevalence of obesity/overweight reveals that environmental factors must be influencing this system, and why some people are more susceptible to weight gain in a given environment is not fully understood [(2)]. In this issue, Fang et al. [(3)] present an interesting and thorough set of experiments that demonstrate how fat content in diet affects defended body weight in C57BL/6N mice. By changing the macronutrient composition (fat and carbohydrate) of diets and undertaking switches in diet at different ages (young and adult) and for different durations (4, 8, or 24 weeks), as well as putting mice through rounds of weight gain and weight loss (yo-yo dieting), they provide strong evidence that the major driver of defended body weight in these animals is the amount of fat within the diet. The key takeaway message is that higher-fat diets (HFDs, i.e., diets with 45% fat or more) cause defense of an elevated body weight plateau, whereas lower-fat diets (LFDs, i.e., diets with 10% or 25% fat) cause defense of a lower body weight plateau irrespective of the age at which the diets start or their duration. Furthermore, HFD- and LFD-fed animals showed similar physiology to a 16-hour fast, and switching mice back to LFDs after HFD feeding caused rapid and sustained weight loss, with most groups returning to the LFD-fed weight. They suggest that HFDs do not impede normal physiological defense of body weight but rather cause an increase to a new defended body weight. This paradigm shift is subtle but important. Although understanding the mechanisms behind these findings is beyond the scope of the paper, increases in circulating lipids from diets have been causally linked to inflammation of the hypothalamus and may, in part, explain the present findings [(4)]. Of course, humans are exposed to many different variables that are hard to replicate in rodent models. For example, workers are much more sedentary than in the past, numerous excess calories are consumed through simple sugars found in soft drinks, and we undertake numerous activities and hobbies that directly affect our daily metabolic rate. All of these parameters likely contribute to our defended body weight; however, the diet likely remains one of the major modifiable inputs. The search for the molecular underpinnings of defense of body weight will continue to evolve with each new study adding to our overall understanding of this important physiological regulation; however, this study [(3)] clearly demonstrates that fat content seems directly implicated in body weight regulation. The type of food we eat likely influences the system of how our body weight is regulated, and understanding these interactions is crucial. This study suggests that eating diets high in fat may result in the overconsumption of calories leading to elevated body weight. Would you like meringue and gruyère double cream just after having eaten a large fondue? Of course you would. Open access funding provided by Universite de Fribourg. The author declared no conflict of interest.

Weight cycling induces innate immune memory in adipose tissue macrophages.

Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages. Bone marrow derived macrophages were primed with palmitic acid or adipose tissue conditioned media in a culture model of innate immune memory. Mice also put on low fat or high fat diets over 14-27 weeks to induce weight gain, weight loss, and weight cycling. Priming cells with palmitic acid or adipose tissue conditioned media from obese mice increased maximal glycolysis and oxidative phosphorylation and increased LPS-induced TNFα and IL-6 production. Palmitic acid effects were dependent on TLR4 and impaired by methyltransferase inhibition and AMPK activation. While weight loss improved glucose tolerance in mice, adipose macrophages were primed for greater activation to subsequent stimulation by LPS ex vivo as measured by cytokine production. In the model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNFα, suggesting that weight loss can also prime macrophages for heighted activation to weight regain. Together, these data suggest that weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.

Repercussions of absolute and time-rated BMI "yo-yo" fluctuations on cardiovascular stress-related morbidities within the vascular-metabolic CUN cohort.

The association between body mass index (BMI) fluctuation and BMI fluctuation rate with cardiovascular stress morbidities in a Caucasian European cohort was evaluated to ascertain the impact of weight cycling. A total of 4,312 patients of the Vascular-Metabolic CUN cohort (VMCUN cohort) were examined and followed up during 9.35 years ( ± 4.39). Cox proportional hazard ratio analyses were performed to assess the risk of developing cardiovascular stress-related diseases (CVDs) across quartiles of BMI fluctuation, measured as the average successive variability (ASV) (ASV = |BMIt0 - BMIt1| + |BMIt1 - BMIt2| + |BMIt2-BMIt3| +…+ |BMItn - 1 - BMItn|/n - 1), and quartiles of BMI fluctuation rate (ASV/year). There were 436 incident cases of CVD-associated events involving 40,323.32 person-years of follow-up. A progressively increased risk of CVD in subjects with greater ASV levels was found. Also, a higher level of ASV/year was significantly associated with an increased risk of developing CVD stress independent of confounding factors with a value of 3.71 (95% CI: 2.71-5.07) for those in the highest quartile and 1.82 (95% CI: 1.33-2.50) for those in the third quartile. The BMI fluctuation rate seems to be a better predictor than BMI fluctuation of the potential development of cardiovascular stress morbidities. The time-rated weight fluctuations are apparently more determinant in increasing the risk of a CVD than the weight fluctuation itself, which is remarkable in subjects under "yo-yo" weight patterns for precision medicine.

Dieting Behavior Characterized by Caloric Restriction and Relation to Sleep: A Brief Contemporary Review.

There is sufficient evidence showing that greater sleep quality improves weight loss outcomes achieved through dietary modifications; however, the effects of dietary modifications such as caloric restriction on sleep outcomes is less established. Caloric restriction is a commonly recommended weight-loss method, yet it may result in short-term weight loss and subsequent weight regain, known as "weight cycling", which has recently been shown to be associated with both poor sleep and worse cardiovascular health. The purpose of this brief narrative review was to summarize the evidence from recent studies of the effects of caloric restriction on sleep. Six articles were identified that specifically measured effects of a caloric restriction-based intervention on aspects of sleep as primary or secondary outcomes. Most research to date indicates that caloric restriction improves sleep outcomes including sleep quality and sleep onset latency. However, the relation between caloric restriction and sleep duration is less clear. Given the mixed results and the potential for severe caloric restriction to lead to weight cycling, future studies are needed to clarify how caloric restriction affects sleep and the potential implications for weight-management efforts.

Type 2 Diabetes Incidence and Mortality: Associations with Physical Activity, Fitness, Weight Loss, and Weight Cycling.

Cardiometabolic diseases, including cardiovascular disease (CVD) and type 2 diabetes (T2D), are the leading cause of death globally. Because T2D and obesity are strongly associated, weight loss is the cornerstone of treatment. However, weight loss is rarely sustained, which may lead to weight cycling, which is associated with increased mortality risk in patients with T2D. Meta-analyses show that weight loss is not generally associated with reduced mortality risk in T2D, whereas weight cycling is associated with increased all-cause and CVD mortality. This may be attributable in part to increased variability in CVD risk factors that often accompany weight cycling, which studies show is consistently associated with adverse CVD outcomes in patients with T2D. The inconsistent associations between weight loss and mortality risk in T2D, and consistent findings of elevated mortality risk associated with weight cycling, present a conundrum for a weight-loss focused T2D prevention and treatment strategy. This is further complicated by the findings that among patients with T2D, mortality risk is lowest in the body mass index (BMI) range of ~25-35 kg/ . Because this "obesity paradox" has been consistently demonstrated in 7 meta-analyses, the lower mortality risk for individuals with T2D in this BMI range may not be all that paradoxical. Physical activity (PA), cardiorespiratory fitness (CRF), and muscular fitness (MF) are all associated with reduced risk of T2D, and lower risk of CVD and all-cause mortality in individuals with T2D. Reducing sedentary behavior, independent of PA status, also is strongly associated with reduced risk of T2D. Improvements in cardiometabolic risk factors with exercise training are comparable to those observed in weight loss interventions, and are largely independent of weight loss. To minimize risks associated with weight cycling, it may be prudent to adopt a weight-neutral approach for prevention and treatment of individuals with obesity and T2D by focusing on increasing PA and improving CRF and MF without a specific weight loss goal.

Long Term Weight Cycling Affects Fecal Microbiota of Mice.

Fighting obesity and associated comorbidities through dieting is not always sustained and results in a subsequent weight gain, a phenomenon referred to as weight cycling. Diet is among the most important factors in modifying the composition of gut microbiota. The objective of this work is to determine whether weight cycling affects the composition and the predicted function of mouse fecal bacteria on a long-term basis. Mice fed for 40 weeks with either high fat (HF), low fat (LF), or cycled diets (starting and ending by one of the two diets, and the reverse) exhibit a bacterial profile specific to each of the four groups. A higher proportion of Firmicutes and Bacteroidota phyla are observed in mice on Hf and LF diet, respectively. The proportion of functions dedicated to amino acid metabolism is higher in mice on HF or LF/HF diets, whereas the mice on LF or HF/LF diets have a higher proportion of functions involve in carbohydrate metabolism and vitamin B biosynthesis. Compared to continuous HF or LF diets, cyclic diet specifically alters the composition and function of the mouse fecal microbiota, suggesting that fight against weight gain should be considered on a long-term basis.

Yo-Yo Dieting: Mixed Messages for β-Cell Plasticity.

Yo-Yo Dieting: Mixed Messages for β-Cell Plasticity.

Body mass index trajectories and their predictors in undergraduate students from Canada: Results from the GENEiUS study

Objective: To explore the patterns and predictors of body mass index (BMI) change among undergraduate students from Ontario (Canada). Participants: 68 undergraduate students were followed longitudinally for 3 years with anthropometric data collected bi-annually. Methods: BMI measurements were plotted to generate individual BMI trajectory curves, which were categorized, based on the observed trajectory pattern. Within and between group comparisons of BMI were conducted via nonparametric paired tests. The association of baseline BMI, sex, and ethnicity with BMI trajectory type was assessed using multinomial logistic regression. Results: Four BMI trajectory types were observed: “stable weight” (n = 15, 22.1%), “weight gain” (n = 30, 44.1%), “weight loss” (n = 12, 17.6%), and “weight cycling” (n = 11, 16.2%) trajectories. Higher baseline BMI was significantly associated with the “weight gain,” “weight loss,” and the “weight cycling” trajectories as compared to the “stable weight” trajectory type. Conclusions: Our findings demonstrate an association between high baseline BMI and “nonstable” subsequent BMI change patterns among Canadian students.

Weight Cycling Impairs Pancreatic Insulin Secretion but Does Not Perturb Whole-Body Insulin Action in Mice With Diet-Induced Obesity.

In the setting of obesity and insulin resistance, glycemia is controlled in part by β-cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared with those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.

Lifestyle behaviors, metabolic disturbances, and weight gain in psychiatric inpatients treated with weight gain-associated medication

Many psychiatric patients suffer from overweight/obesity and subsequent metabolic disturbances, where psychotropic medication is one of the main contributors. However, the magnitude of weight gain ranges individually, which leads to questioning the role of other contributors like lifestyle factors. The present study investigated several lifestyle factors among psychiatric inpatients, their relation to biological factors, and their predictive capability for weight gain during treatment. Using a naturalistic observational study design, psychiatric inpatients of all diagnoses were followed for 4 weeks from the start of treatment with weight gain-associated medication. N = 163 participants entered the study. Lifestyle factors were assessed by patient self-report questionnaires. Body weight change over time was calculated relative to baseline body weight. Our study provides three main findings: (1) Obesity and/or metabolic syndrome (metSy) were associated with emotional eating (disinhibition), craving for fast food and sweets, and weight cycling. (2) Patients without metSy and normal BMI experienced increased sweets craving (also for women), a more positive attitude towards drugs, and an improvement of affect (also for men). (3) Sex, presence of metSy and/or drug dosage interacted with disinhibition change, sweets craving change (trend), and fast food craving change to predict weight change over time. Furthermore, drug attitude change interacted with BMI, drug dosage, and presence of metSy to predict weight change. Lifestyle factors, especially eating behaviors, are related to metabolic disturbances and predict weight gain in interaction with clinical parameters.

SAT044 - Repeated weight cycling in obese mice improves hepatic inflammation

SAT044 - Repeated weight cycling in obese mice improves hepatic inflammation

Impairment of left ventricular diastolic function and exercise capacity after yoyo dieting in female mice with or without ovariectomy-induced post-menopausal condition

Follow-up studies show that weight gain in women proportionally increases the risk of coronary heart disease and that weight cycling is associated with adverse cardiometabolic markers. Moreover, women after menopause are prone to weight gain. To work out a protocol responsible for weight fluctuation and to measure the cardiac functional consequences after a final weight loss, in mice having undergone or not an ovariectomy (OVX). Five-month-old female underwent OVX or not. Starting 5 days after surgery, mice were subjected to Yoyo dieting with successive periods (I, II, III) of a biphasic alternation of a high fat diet (HFD) (4-week constant phase of HFD60%) followed by standard diet (SD) (phase of 4, 6, 10 weeks for period I, II, III, respectively). Non-OVX control (CTL) mice were maintained on SD. At the end of the last SD phase, the global metabolism was evaluated by an insulin tolerance test and echo-MRI, the blood pressure was measured by plethysmography, the exercise capacity was evaluated on treadmill, then the left ventricular (LV) function was assessed by ultrasound and invasive hemodynamics. Body weight in Yoyo and OVX-Yoyo mice was higher to that of CTL mice at the end of period III. Moreover, the first phase of HFD resulted in a higher weight gain in OVX-yoyo mice, which kept bigger than Yoyo mice until the end of the protocol, however without difference in body composition. There was decreased insulin sensitivity in both Yoyo and Yoyo-OVX mice compared to CTL. There was no difference in blood pressure nor in LV fractional shortening between groups. Invasive hemodynamics showed no difference in LV-end diastolic pressure (LVEDP) but an increased LV end-diastolic pressure volume relation (LVEDPVR) in OVX-Yoyo mice, indicating decreased compliance. LV weight was increased in Yoyo mice only. Treadmill stress test showed decreased running duration for OVX-Yoyo mice only ( Fig. 1 ). In female mice subjected to the same Yoyo diet protocol, those in post-menopausal condition after OVX show an increased risk of developing heart failure with preserved ejection fraction and reduced exercise capacity.

Preclinical Efficacy of INST3399, a Synthetic Novel PKCbeta Inhibitor, for the Treatment of Obesity and Fatty Liver Disease

ObjectivesThe prevalence of obesity has increased over the last few decades reaching epidemic proportions. Clearly, public health efforts and anti obesity agents presently in use are inadequate for curbing the obesity epidemic. Currently existing FDA-approved anti-obesity drugs are specific receptor-targeted drugs that focus on reducing energy intake. Energy intake reduction is equivalent to calorie-restricted dieting and is prone to weight cycling because it decreases muscle mass, leading to reduced metabolic function and energy expenditure. Hence, long-term weight loss is difficult to achieve. In consideration of the aforementioned hurdles, a promising anti-obesity drug should consist of multi-functional effects leading to energy expenditure. We previously demonstrated that mice with systemic PKCβ deficiency displayed many of the features one would desire in individuals treated with an ideal anti-obesity drug; elevated metabolic rate, which contribute to protection from diet-induced obesity, hepatic steatosis, and insulin-resistance (Hepatology 49:1525,2009; J. Lipid Res. 286:22,795,2011). We recently reported that depletion of hepatocyte-specific PKCβ recapitulates many of the beneficial features of systemic PKCbeta deficient mice (Mol. Metab. 44: e101133,2021; JCI Insight 6: e149023,2021). These results provide compelling evidence that PKCβ is an important therapeutic target for the treatment of obesity, as well as its related metabolic complications.MethodsOur aim is to evaluate therapeutic effects of a novel PKCβ inhibitor, INST3399 to treat obesity and fatty liver disease in a high-fat diet-induced obese C57BL/6J mouse model.ResultsINST3399 is a novel PKCβ inhibitor, which inhibits this kinase by a mechanism different from a well-known alternative ruboxistaurin. INST3399 inhibits PKCβ in the basal state, about >5-times more potent than ruboxistaurin and exhibit more than >100-fold selectivity for PKCβ versus PKCα. Our data demonstrate that INST3399 is safe and able to decrease the degree of obesity and fatty liver disease.ConclusionsINST3399 is a promising novel drug candidate for the pharmacological treatment of obesity and associated comorbidities. Moreover, INST3399 could further evolve as a novel treatment to manage other metabolic conditions with excessive PKCβ expression.Funding SourcesNIH HL138198; Instacare Funds.

The Effects of Acupressure on Menopausal Symptoms: A Randomized Controlled Study

Objectives: The aim of this study was to see how weight cycling affected women's nutritional health and their risk of developing Type 2 diabetes (T2DM). Materials and Methods: Between November 2018 and May 2019, 80 women aged 18 to 65 years old applied to the Nutrition and Diet Department of a Private Medical Center and consented to participate in the study. A questionnaire form was applied to the participants, anthropometric measurements and biochemical blood parameters were evaluated. The Finnish Diabetes Risk Score (FINDRISK) was used to determine the risk of T2DM. Results: 55 of the 80 women included in the study (68.8%) entered the weight cycle, while 25 (31.2%) did not enter the weight cycle. In terms of body weight, BMI, waist circumference, body fat mass, and HOMA-IR values, there was a statistically significant difference between the groups (p0.05). While the amount of total energy, protein, fat, cholesterol, and omega-6 fatty acids in the daily diet of women who entered the weight cycle was higher than those who did not enter the weight cycle, it was observed that the intake of carbohydrates and omega-3 fatty acids were lower (p&gt;0.05). There was no significant difference between the groups regarding the FINDRISK score (p&gt;0.05). Conclusion: Weight cycling is particularly frequent among women nowadays, and it is a significant risk factor for chronic illnesses in the coming years. Although this study's duration and sample number are limited, the data obtained emphasizes the effects of weight cycling on health.