Adiposity, Body Composition Measures, and Breast Cancer Risk in Korean Premenopausal Women.

Objective: To investigate the association between body composition parameters and breast cancer (BC) risk in premenopausal women. Design, Setting, and Participants: Prospective cohort study using data from the Kangbuk Samsung Cohort Study. Participants were women aged 20 to 54 years who were enrolled from 2011 to 2019 and followed up for BC development until December 31, 2020. Data were analyzed from June to August 2023. Exposures: Trained nurses conducted anthropometric measurements and assessed body composition using segmental bioelectric impedance analysis. The analysis encompassed adiposity measures such as body mass index (BMI), waist circumference, and body composition parameters, including muscle mass, fat mass, ratio of muscle mass to weight, ratio of fat mass to weight, and fat mass index. Main outcomes and measures: Adjusted hazard ratios (aHR) for BC during the follow-up period. Results: Among 125 188 premenopausal women, the mean (SD) age was 34.9 (6.3) years. During a mean (range) follow-up of 6.7 (0.5-9.9) years, 1110 incident BC cases were identified. The mean (SD) BMI and waist circumference were 21.6 (3.1) and 75.3 (8.2) cm, respectively. Higher BMI and waist circumference were associated with decreased risk, with an aHR of 0.89 (95% CI, 0.84-0.95) per SD increase in BMI and 0.92 (95% CI, 0.86-0.98) per SD increase in waist circumference. A higher ratio of fat mass to weight was associated with decreased BC risk (aHR, 0.92; 95% CI, 0.86-0.99 per SD increase), whereas the opposite trend was observed for the ratio of muscle mass to weight, with an aHR of 1.08 (95% CI, 1.02-1.15) per SD increase. The results remained consistent even after additional adjustments for height in the model. The fat mass index was also inversely associated with BC risk, with an HR of 0.90 (95% CI, 0.85-0.97) per SD increase. Conclusions and Relevance: In this cohort study of premenopausal women, a higher level of adiposity, represented by increased BMI, waist circumference, and fat mass, was consistently associated with decreased breast cancer risk. Conversely, muscle mass and its ratio to weight displayed opposite or inconsistent patterns. These findings suggest an inverse association between excess adiposity and the risk of BC in premenopausal women, confirming earlier findings that BMI is an indirect measure of adiposity.

Cross-sectional association study of hedonic hunger, self-control, cognitive distortion, and well-being with adiposity measures among a sample of urban Malaysian adults.

BACKGROUND: We assessed the association of hedonic hunger, self-control (impulsivity and restraint), cognitive distortion (CD), and well-being with adiposity measures such as waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body mass index (BMI), total body fat (TBF), subcutaneous fat (SF), visceral fat level (VFL), skeletal muscle percentage (SM), and resting metabolism (RM), among a sample of urban Malaysian adults at Sunway University and Sunway College, Selangor, Malaysia. METHODS: Among 186 participants (M/F = 51/135; aged 22.1 ± 5.0), psychometrics were assessed using Power of Food Scale (PFS), Brief Self-Control Scale, CD Questionnaire (CD-Quest), and WHO-5 Well-being Index. Blood pressures, anthropometrics and body compositions were also measured using standard methods and bioimpedance. RESULTS: Men had significantly higher well-being, but lower overall self-control, impulsivity and Food Available hedonic hunger. Those with moderate/severe CD had higher odds ratio (OR) of having high central adiposity, compared with those with absent/slight CD (OR: 2.52;95% CI: 1.14, 5.61; p = 0.023 for WC and OR: 2.50; 95% CI: 1.19, 5.23; p = 0.015 for WHR). Higher CD and PFS scores were strongly significantly correlated with higher systolic blood pressure (SBP), WC, WHR, WHtR, BMI, TBF, SF, VFL and RM. Lower self-control was weakly correlated with higher WC, while lower impulsivity and restraint were weakly correlated with higher VFL. Those who were overweight, obese, and in high TBF class had significantly higher PFS Aggregate Factor scores. Food Available and Food Present scores, but not Food Tasted, were also significantly higher among overweight participants. CONCLUSIONS: Higher hedonic hunger and CD were associated with higher SBP and all adiposity measures. Overweight participants had higher hedonic hunger in the context of ready availability and physical presence of highly palatable foods. Lower self-control was weakly correlated with higher central adiposity; lower impulsivity and restraint were weakly correlated with higher visceral adiposity. These findings have provided some insights into the cognitive factors underlying adiposity.

Effects of maternal exercise on infant mesenchymal stem cell mitochondrial function, insulin action, and body composition in infancy.

Maternal exercise (ME) has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy-sensing and redox-sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.

Association of longitudinal trajectories of general and abdominal adiposity during middle age with mental health and well-being in late life: A prospective analysis.

Single measures of adiposity markers, such as body mass index (BMI) and waist circumference (WC), are associated with adverse mental health outcomes; however, long-term patterns of adiposity and their health effects remain unclear. The current study assessed adiposity trajectories during a 14-year span beyond middle age and their relevance to mental well-being in late life, and the contribution of genetic and lifestyle factors to the trajectories. Based on a nationally representative sample with longitudinal anthropometric measures, adiposity trajectories were identified by latent mixture modeling, and logistic regression model was used to estimate their associations with mental well-being, with adjustment for confounders. Of the 3491 eligible participants included (mean [SD] age, 69.5 [8.9] years), five discrete BMI and four WC trajectory patterns were identified over 14 years. Compared with the low-stable BMI group (range, 22.8 to 22.9 kg/m²; representing stable healthy body weight), the high-stable group (range, 34.3 to 35.4 kg/m²; stable obese) was associated with increased risk of depression (odds ratio [OR], 1.63; 95 % CI, 1.28-2.07) and low subjective well-being (OR, 1.35; 95 % CI, 1.02-1.79). Compared with the low-stable WC group (range, 75 to 79 cm healthy WC), the high-increasing group (range, 114 to 121 cm) was associated with increased risk of depression (odds ratio [OR], 1.64; 95 % CI, 1.19-2.25) and low well-being (OR, 1.48; 95 % CI, 1.01-2.16). The adiposity trajectories, especially the high-stable/increasing groups, were driven by genetic factors in a dose-response manner, whereas the high/moderate-increasing groups were also behaviorally related. This longitudinal cohort study reveals that stably high trajectory patterns of central and general adiposity during middle age were associated with higher risk of depression and low well-being in late life. The findings indicate the importance of weight management beyond middle age, such as adherence to a healthy lifestyle, in promoting mental health and well-being.

The complex associations between adiposity, fitness, mental wellbeing and neurocognitive function after exercise: A randomized crossover trial in preadolescent children.

The aim of the present study was to examine the associations of adiposity and fitness on the preadolescent brain's response to acute exercise. In a sample of 58 children (ages 8-10; 19 females), demographic measures of age, sex, IQ, puberty, and socioeconomic status were considered. Children participated in a randomized crossover study, whereby they completed two different interventions; seated rest or treadmill walking, counterbalanced across participants. Associations between adiposity measures (standardized body mass index [BMI-Z], whole body percent fat [%Fat], visceral adipose tissue [VAT]), cardiorespiratory fitness measures (VO2max and Fat-Free VO2) were assessed on self-reported measures of mental wellbeing, and cognitive performance (response accuracy, reaction time) and neuroelectric (P3 amplitude and latency) indices of a Go/NoGo task following both exercise and rest interventions. Higher adiposity (whole-body percent fat, BMI-Z) was associated with higher trait anxiety (P's≤0.05) and disordered eating (P's≤0.05) scores. Higher fitness (VO2max) was associated with lower childhood depression scores (P=0.02). Regression analyses yielded specific post-exercise neurocognitive associations with adiposity-related (VAT, BMI-Z), and fitness-related (FF-VO2) outcomes, after controlling for post-rest neurocognitive outcomes. VAT was positively associated with post-exercise P3 ERP Latency for the Go task (P≤0.001); BMI-Z was negatively associated with P3 ERP amplitudes for the Go task (P's≤0.005); FF-VO2 was negatively associated with P3 ERP latency for the Go/NoGo task (P's≤0.05), and positively associated with NoGo task accuracy (P≤0.001). Overall, adiposity and fat-free fitness measures yield sensitive and differential associations with neurocognitive performance after exercise and after rest interventions.

Associations of radiologic characteristics of the neonatal hypothalamus with early life adiposity gain.

BACKGROUND: The mediobasal hypothalamus (MBH) is a key brain area for regulation of energy balance. Previous neuroimaging studies suggest that T2-based signal properties indicative of cellular inflammatory response (gliosis) are present in adults and children with obesity, and predicts greater adiposity gain in children at risk of obesity. OBJECTIVES/METHODS: The current study aimed to extend this concept to the early life period by considering if, in full-term healthy neonates (up to n = 35), MRI evidence of MBH gliosis is associated with changes in early life (neonatal to six months) body fat percentage measured by DXA. RESULTS: In this initial study, neonatal T2 signal in the MBH was positively associated with six-month changes in body fat percentage. CONCLUSION: This finding supports the notion that underlying processes in the MBH may play a role in early life growth and, by extension, childhood obesity risk.

The longitudinal association of adipose-to-lean ratio with incident cardiometabolic morbidity: The CARDIA study.

AIM: To assess the association of adipose-to-lean ratio (ALR) with incident type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia in middle adulthood. METHOD: Black and White Coronary Artery Risk Development in Young Adults participants without T2DM, hypertension, or dyslipidemia in 2005-06 (baseline) were included. Baseline adipose and lean mass were assessed via dual-energy X-ray absorptiometry. ALR was calculated as adipose divided by lean mass and then standardized within sex strata. Single time-point incident morbidity was assessed every five years from baseline through 2016. Cox proportional hazards regression was used to estimate hazard ratios (HR) for morbidity over 10 years per 1-SD increment in ALR adjusted for cardiovascular risk factors. RESULT: The cumulative incidence of T2DM was 7.9 % (129 events/N = 1643; 16,301 person-years), 26.7 % (485 events/N = 1819; 17,895 person-years) for hypertension, and 49.1 % (435 events/N = 855, 8089 person-years) for dyslipidemia. In the adjusted models, ALR was positively associated with a risk of T2DM (HR [95 % CI]; 1.69 [1.31, 2.19]) and hypertension (1.23 [1.08, 1.40]). There was no significant interaction between ALR and sex for any morbidity. CONCLUSION: ALR in middle adulthood is associated with incident T2DM and hypertension. The extent to which localized body composition measures might inform morbidity risk merits further investigation.

The effects of initial and subsequent overweight or obesity on hypertension in the middle age.

The aims of our study were to examine whether initial or subsequent adiposity status had a greater effect on hypertension. We collected data in 1992 and again in 2007 from the same group of 597 individuals in the middle age. The subjects were classified into four groups: individuals with a normal body mass index (BMI) in 1992 and 2007 were in Group I; those with a normal BMI in 1992, but became overweight or obese in 2007 were in Group II; those who were overweight or obese in 1992, but had a normal BMI in 2007 were in Group III; and those who were overweight or obese in 1992 and 2007 were in Group IV. Their demographic data were recorded. The relationship between adiposity status and hypertension was analyzed using logistic regression model. The cumulative incidence of hypertension was 35.5%, 56.3%, 50.0%, and 65.1% for Group I to IV, respectively. Compared with Group I, after adjusted factors, the hazard ratio (HR) was 1.80 for Group II (P = .001), 1.40 for Group III (P = .150), and 2.31 for Group IV (P < .001). Adiposity status in 2007 could predict hypertension (OR = 2.5, P < .001), as opposed to the initial adiposity status (P = .148). Subsequently adiposity status could have major effects on hypertension. Our society is very short of public health resources, particularly in developing countries, we should pay more attention to current adiposity status and encourage middle-aged people to lose weight.

The potential mechanisms underlying the modulating effect of perirenal adipose tissue on hypertension: Physical compression, paracrine, and neurogenic regulation.

Hypertension, a prevalent global cardiovascular disease, affects approximately 45.4 % of adults worldwide. Despite advances in therapy, hypertension continues to pose a significant health risk due to inadequate management. It has been established that excessive adiposity contributes majorly to hypertension, accounting for 65 to 75 % of primary cases. Fat depots can be categorised into subcutaneous and visceral adipose tissue based on anatomical and physiological characteristics. The metabolic impact and the risk of hypertension are determined more significantly by visceral fat. Perirenal adipose tissue (PRAT), a viscera enveloping the kidney, is known for its superior vascularisation and abundant innervation. Although traditionally deemed as a mechanical support tissue, recent studies have indicated its contributing potential to hypertension. Hypertensive patients tend to have increased PRAT thickness compared to those without, and there is a positive correlation between PRAT thickness and elevated systolic blood pressure. This review encapsulates the anatomical characteristics and biogenesis of PRAT. We provide an overview of the potential mechanisms where PRAT may modulate blood pressure, including physical compression, paracrine effects, and neurogenic regulation. PRAT has become a promising target for hypertension management, and continuous effort is required to further explore the underlying mechanisms.

Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

Grip strength positively correlates with blood pressure in individuals with abnormal adiposity.

Although strong positive correlations exist between grip strength and cardiovascular health, the association between grip strength and blood pressure (BP) is less clear. In this regard, a more precise relationship between grip strength and BP may be revealed by considering adiposity. We examined the association between grip strength and BP in 9424 individuals aged 18-92 years, while controlling for or stratifying by body mass index (BMI) or body fat (BF)%. Grip strength, BP and BF% were determined using dynamometry, sphygmomanometry and dual-energy x-ray absorptiometry. Overall, those with elevated BP had greater grip strength than those with normal BP (39.17 kg vs 38.38 kg, p < 0.001); however, following stratification this was only observed in overweight or obese individuals (42.08 kg vs 41.10 kg, p = 0.003 and 41.34 kg vs 40.03 kg, p = 0.033), and those within the highest BF% tertile (37.95 kg vs 36.52 kg, p < 0.001). Overall, higher grip strength was associated with an increased odds for elevated BP (OR = 1.014, 95% CI = 1.004-1.024, p = 0.004); however, after stratification the increased odds was only observed in overweight or obese individuals (OR = 1.025, 95% CI = 1.010-1.039, p < 0.001 and OR = 1.018, 95% CI = 1.004-1.031, p = 0.010), and those within the highest BF% tertile (OR = 1.036, 95% CI = 1.022-1.051, p < 0.001). Individuals with low grip strength and high BF% had lower odds for elevated BP (OR = 0.514, 95% CI = 0.341-0.775, p = 0.002), whereas those with low grip strength and low BF% had higher odds for elevated BP (OR = 2.162, 95% CI = 1.026-4.555, p = 0.043). Our findings show that higher grip strength is related to higher BP in overweight or obese individuals, or those with a high BF%. Having a BMI < 25 kg/m2 or lower BF% may neutralise this association.

Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk.

This review analyzes the published evidence regarding maternal factors that influence the developmental programming of long-term adiposity in humans and animals via the central nervous system (CNS). We describe the physiological outcomes of perinatal underfeeding and overfeeding and explore potential mechanisms that may mediate the impact of such exposures on the development of feeding circuits within the CNS-including the influences of metabolic hormones and epigenetic changes. The perinatal environment, reflective of maternal nutritional status, contributes to the programming of offspring adiposity. The in utero and early postnatal periods represent critically sensitive developmental windows during which the hormonal and metabolic milieu affects the maturation of the hypothalamus. Maternal hyperglycemia is associated with increased transfer of glucose to the fetus driving fetal hyperinsulinemia. Elevated fetal insulin causes increased adiposity and consequently higher fetal circulating leptin concentration. Mechanistic studies in animal models indicate important roles of leptin and insulin in central and peripheral programming of adiposity, and suggest that optimal concentrations of these hormones are critical during early life. Additionally, the environmental milieu during development may be conveyed to progeny through epigenetic marks and these can potentially be vertically transmitted to subsequent generations. Thus, nutritional and metabolic/endocrine signals during perinatal development can have lifelong (and possibly multigenerational) impacts on offspring body weight regulation.

Circadian misalignment impacts the association of visceral adiposity with metabolic syndrome in adolescents.

STUDY OBJECTIVES: Although insufficient sleep is a risk factor for metabolic syndrome (MetS), the circadian timing of sleep (CTS) is also involved in cardiac and metabolic regulation. We examined whether delays and deviations in the sleep midpoint (SM), a measure of CTS, modify the association between visceral adipose tissue (VAT) and MetS in adolescents. METHODS: We evaluated 277 adolescents (median 16 years) who had at least 5 nights of at-home actigraphy (ACT), in-lab polysomnography (PSG), dual-energy X-ray absorptiometry (DXA) scan, and MetS score data. Sleep midpoint (SM), sleep irregularity (SI), and social jetlag (SJL) were examined as effect modifiers of the association between VAT and MetS, including waist circumference, blood pressure, insulin resistance, triglycerides, and cholesterol. Linear regression models adjusted for demographics, ACT-sleep duration, ACT-sleep variability, and PSG-apnea-hypopnea index. RESULTS: The association between VAT and MetS was significantly stronger (p-values for interactions < 0.001) among adolescents with a schooldays SM later than 4:00 (2.66 [0.30] points increase in MetS score), a SI higher than 1 hour (2.49 [0.30]) or a SJL greater than 1.5 hours (2.15 [0.36]), than in those with an earlier SM (<3:00; 1.76 [0.28]), lower SI (<30 minutes; 0.98 [0.70]), or optimal SJL (<30 minutes; 1.08 [0.45]). CONCLUSIONS: A delayed sleep phase, an irregular sleep-wake cycle, and greater social jetlag on schooldays identified adolescents in whom VAT had a stronger association with MetS. Circadian misalignment is a risk factor that enhances the impact of visceral obesity on cardiometabolic morbidity and should be a target of preventative strategies in adolescents.

Brief Report: Relationship Between Adiposity and Biomarkers of Aging and Frailty Among Adults Aging With HIV.

BACKGROUND: This study examined the relationships among adiposity, handgrip, physical function, inflammation (ie, senescence-associated secretory phenotype chemokines as biomarkers of aging and frailty), and sex hormones in aging people with HIV. METHODS: This cross-sectional exploratory study included 150 people with HIV aged ≥40 years (67.3% of participants were male). Our measures included (1) body mass index and waist circumference as measures of adiposity; (2) handgrip as a measure of muscle strength; (3) short physical performance battery as a measure of physical function; (4) interleukin-6, tumor necrosis factor alpha receptor II, high sensitivity C-reactive protein, C-X-C motif chemokine 10, and C-X3-C motif chemokine ligand 1 also known as fractalkine as senescence-associated secretory phenotype chemokines; and (5) free testosterone, estradiol, sex hormone-binding globulin, and dehydroepiandrosterone as sex hormones. Quantile regression analyses were used to identify relationships among inflammatory markers and hormones with age, adiposity, handgrip, and physical function. RESULTS: Overall, 74% (n = 111) of participants were classified as overweight or obese and 53.3% (n = 80) presented with abdominal obesity. After controlling for age and sex, body mass index was positively associated with estradiol (ß = 0.043, P < 0.01), and waist circumference was positively associated with high sensitivity C-reactive protein (ß = 2.151, P < 0.01). After controlling for sex, age was positively associated with C-X-C motif chemokine 10 (ß = 0.024, P = 0.03) and tumor necrosis factor alpha receptor II (ß = 2.205, P = 0.01). After controlling for age and sex, short physical performance battery was negatively associated with dehydroepiandrosterone (ß = -0.004, P = 0.01); no statistically significant associations were observed for handgrip. CONCLUSION: Adiposity levels and aging were associated with inflammation (ie, C-X-C motif chemokine 10, tumor necrosis factor alpha receptor II, and high sensitivity C-reactive protein) among people with HIV aged 40 years and older.

Associations of general and central adiposity with hypertension and cardiovascular disease among South Asian populations: a systematic review and meta-analysis.

BACKGROUND: The relevance of measures of general and central adiposity for cardiovascular disease (CVD) risks in populations of European descent is well established. However, it is less well characterised in South Asian populations, who characteristically manifest larger waist circumferences (WC) for equivalent body mass index (BMI). This systematic review and meta-analysis provide an overview of the literature on the association of different anthropometric measures with CVD risk among South Asians. METHODOLOGY: MEDLINE and Embase were searched from 1990 to the present for studies in South Asian populations investigating associations of two or more adiposity measures with CVD. Random-effects meta-analyses were conducted on the associations of BMI, WC and waist-to-hip ratio (WHR) with blood pressure, hypertension and CVD. Quality assessment was performed using the Newcastle-Ottawa scale. RESULTS: Titles and abstracts were screened for 7327 studies, yielding 147 full-text reviews. The final sample (n=30) included 2 prospective, 5 case-control and 23 cross-sectional studies. Studies reported generally higher risks of hypertension and CVD at higher adiposity levels. The pooled mean difference in systolic blood pressure (SBP) per 5 kg/m2 higher BMI was 3 mmHg (2.90 (95% CI 1.30 to 4.50)) and 6 mmHg (6.31 (95% CI 4.81 to 7.81) per 13 cm larger WC. The odds ratio (OR) of hypertension per 5 kg/m2 higher BMI was 1.33 (95% CI 1.18 to 1.51), 1.45 (95% CI 1.05 to 1.98) per 13 cm larger WC and 1.22 (95% CI 1.04 to 1.41) per 0.1-unit larger WHR. Pooled risk of CVD for BMI-defined overweight versus healthy-weight was 1.65 (95% CI 1.55 to 1.75) and 1.48 (95% CI 1.21 to 1.80) and 2.51 (95% CI 0.94 to 6.69) for normal versus large WC and WHR, respectively. Study quality was average with significant heterogeneity. CONCLUSIONS: Measures of both general and central adiposity had similar, strong positive associations with the risk of CVD in South Asians. Larger prospective studies are required to clarify which measures of body composition are more informative for targeted CVD primary prevention in this population.

A protein kinase C α and ß inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.

Plasma IGFBP-2 levels reveal heterogeneity in hepatic fat content in adults with excess visceral adiposity.

Lay summary: Obesity is frequently accompanied by a fatty liver. However, some individuals with high abdominal fat levels nevertheless have low levels of liver fat. Reasons for such discordant phenotypes are unclear. In this paper, we report that among asymptomatic individuals with high levels of visceral fat, low concentrations of IGFBP-2 in the circulation were associated with significantly higher hepatic fat content compared to those with high IGFBP-2 levels. We conclude that quantification of plasma IGFBP-2 concentrations may be useful to identify the early risk for liver fat accumulation in apparently healthy individuals without cardiovascular symptoms. Aim/hypothesis: Although excess visceral adiposity (VAT) is generally associated with increased liver fat (LF), recent evidence has revealed heterogeneity in LF content among adults with visceral obesity, potentially contributing to specific differences in cardiometabolic outcomes. Reasons for such discordant VAT-LF phenotypes are largely unknown. The present study aimed at assessing whether circulating levels of insulin growth-factor binding protein-2 (IGFBP-2) could be a useful biomarker in the identification of heterogenous and discordant VAT-LF phenotypes. Methods: A sample of 308 middle-aged Caucasian apparently healthy men and women without cardiovascular symptoms were studied for the present cross-sectional analyses. Fasting plasma glucose and lipid levels were assessed and an oral glucose tolerance test was performed. Hepatic fat fraction (HFF) was measured using magnetic resonance spectroscopy whereas VAT was assessed by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants were then classified on the basis of median VAT (81 mL) and IGFBP-2 levels (233 ng/mL). Results: Individuals with high levels of VAT were characterized by higher waist circumference, lower insulin sensitivity, as well as by higher plasma triglyceride and lower HDL-cholesterol levels. Plasma IGFBP-2 levels were inversely correlated with HFF (r = -0.39, p < 0.0001). Among men and women with high levels of VAT, those with low levels of IGFBP-2 had significantly higher HFF (7.5 ± 0.7%), compared to participants with high IGFBP-2 concentrations (3.2 ± 0.5%, p < 0.0001). Conclusion: In the presence of excess VAT, high IGFBP-2 concentrations are associated with low levels of LF. Although additional studies will be necessary to establish causality and further clarify the clinical implications of these observations, these findings are concordant with a novel function of IGFBP-2 in modulating susceptibility to non-alcoholic fatty liver disease (NAFLD) in the presence of visceral obesity.

Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse.

It is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological maternal adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. Moreover, it remains unknown how pregnancy and diet can interact to alter intestinal barrier function. In this study, we investigated the impacts of pregnancy and adiposity on maternal intestinal epithelium morphology, in vivo intestinal permeability, and peripheral blood immunophenotype, using control (CTL) and high-fat (HF) fed non-pregnant female mice and pregnant mice at mid- (embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF-fed mice had reduced small intestine length, ileum crypt depth and villus length. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid- versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid but not late-gestation. The impaired maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity. Maternal adaptations in pregnancy are thus vulnerable to excess maternal adiposity, which may both affect maternal and child health.

Maternal Prenatal Factors and Child Adiposity in Associations with Cardiometabolic Risk Factors in Term-Born Chinese Children at the Age of 2 Years.

Early growth has long-lasting associations with adult metabolic health. However, the association of adiposity with cardiometabolic risk factors in toddlers remains poorly understood. This study aimed to examine the association of maternal prenatal factors and child adiposity with child cardiometabolic risk factors among boys and girls aged 2 years. This was a birth cohort study of 549 term-born children in Shanghai, China, with follow-up data at the age of 2-years. Child anthropometric and adiposity measurements included weight, length, and skinfold thickness (triceps, subscapular, and abdominal). Child cardiometabolic risk factors included random morning plasma glucose, serum insulin, lipids, and systolic and diastolic blood pressure (SBP, DBP). At 2 years, overweight/obesity (weight-for-length z score, ZWFL > 2) was associated with 12.6 (95%CI 7.7, 17.4) mmHg higher SBP, and 7.9 (4.1, 11.8) mmHg higher DBP in boys, with similar results observed in girls. Maternal hypertensive disorders of pregnancy were associated with 3.0 (0.1, 5.8) higher SBP, 3.17 (0.90, 5.44) mmHg higher DBP, 0.24 (0.01,0.47) mmol/L higher plasma glucose, and 0.26 (0.01,0.51) mmol/L higher serum triglycerides after adjustment for child age, sex, and ZWFL. Maternal hypertensive disorders of pregnancy and child overweight/obesity were associated with higher SBP and DBP at the age of 2 years.

An adiposity force induces obesity in humans independently of a normal energy balance system-a thought experiment.

Obesity in humans represents a cumulative retention of a tiny fraction of total energy intake as fat, which is accompanied by growth of the metabolically active, energy-demanding, lean body mass. Since the energy balance regulation operates irrespective of the excess fat storage, availability of the required energy supplies is a permissive condition for obesity development. It occurs predominantly among people genetically predisposed and/or living with social or mental challenges. I propose a theory in which the body responds to social disruptions as threats of a future lack of food by an adiposity force building a reserve of energy independent of the regulation of the energy balance. It is based on the assumption that our evolutionary development required collaboration in gathering and sharing of food, combined with precautionary measures against anticipated failing food supplies. Social challenges are perceived as such threats, which activate the adiposity force through the brain to instigate the growth of fat and lean mass by neuro-hormonal signalling. If both perceived social threats and food abundance continue, the adiposity force pushes the fat accretion process to continue without inhibition by feedback signals from the fat mass, eventually leading to more obesity, and more so among the genetically predisposed. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.