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Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity‐associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high‐fat diet (HFD) for 13 or 26 weeks, whereas age‐matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity‐associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health. High fat diet (HFD) induces typical obesity phenotype in female mice independent of their age and duration of HFD. Young females partially resist inflammatory processes induced by moderate duration (13 weeks) of HFD/obesity while females in advanced age develop full‐scale inflammation, indicating age as a risk factor for obesity associated comorbidities. When HFD/obesity persists for a long duration (26 weeks), even young females develop full‐scale inflammation underlining the importance of early corrective interventions to preserve cognitive function and overall health.

Male reproductive dysfunction is a clinical disease, with a large number of cases being idiopathic. Reproductive disorders have been found in obese (diet-induced obesity and diet-induced obesity-resistant) mice, but the mechanism behind the male reproductive dysfunction between them may be different. The purpose of this study was to explore the possible role and mechanism of miR-34c on sperm production in high-fat-diet-induced obesity-resistant (DIO-R) mice and GC-1 spg cells, which may differ from those in high-fat-diet-induced obesity (DIO) mice. In vivo and in vitro experiments were performed. C57BL/6J mice were fed a high-fat diet for 10 weeks to establish the DIO and DIO-R mouse model. GC-1 spg cells were used to verify the mechanism of miR-34c on sperm production. During in vivo experiments, sperm production damage was found in both DIO and DIO-R male mice. Compared to the control mice, significantly decreased levels of testosterone, LH, activities of acrosome enzyme (ACE), HAse, and activating transcription factor 1 (ATF1) were found in both DIO and DIO-R male mice (p < 0.05). Compared with the control group, the ratio of B-cell lymphoma-2 (Bcl-2)/bcl-2-associated X protein (Bax) in the DIO group was significantly decreased, and the expression level of cleaved caspase-3 was significantly increased (p < 0.05). Compared with the control group, the Bcl-2 protein expression level in the testes of the DIO-R group significantly decreased (p < 0.05). However, the Bax expression level increased. Thus, the Bcl-2/Bax ratio significantly decreased (p < 0.01); however, the factor-related apoptosis (Fas), Fas ligand (FasLG), cleaved caspase-8, caspase-8, cleaved caspase-3, and caspase-3 protein expression levels significantly increased (p < 0.05). Compared with the DIO group, in DIO-R mice, the activities of ACE, ATF1, Bcl-2, and Bcl-2/Bax’s spermatogenesis protein expression decreased, while the apoptosis-promoting protein expression significantly increased (p < 0.05). During the in vitro experiment, the late and early apoptotic ratio in the miR-34c over-expression group increased. MiR-34c over-expression enhanced the expression of apoptosis-related proteins Fas/FasLG and Bax/Bcl-2 while inhibiting the expression of ATF1 and the sperm-associated protein in GC-1 spg cells. DIO and DIO-R could harm sperm production. DIO-R could impair sperm production by inducing the miR-34c-activated apoptosis and spermatogenesis pathway, which may be different from that of DIO.

Obesity is a life-threatening metabolic disorder necessitating urgent development of safe and effective therapy. Currently, limited such therapeutic measures are available for obesity. The present study was designed to develop a novel, safe and effective herbal therapy for the management of obesity. A polyherbal formulation (18KHT01) was developed by homogeneously mixing a specific proportion of crude Quercus acutissima (acorn jelly powder), Camellia sinensis (dry leaf buds), and Geranium thunbergii (dry aerial part) along with Citrus limon (fruit juice). Synergistic antioxidant, antiadipogenic, and anti-obesity activities were evaluated by in vitro as well as in vivo studies. In vitro experiments revealed strong synergistic antioxidant and anti-adipogenic activities of 18KHT01. Molecular assessment of 18KHT01 showed significant down-regulation of vital adipogenic factors such as PPARγ, C/EBPα, aP2, SREBP-1c, FAS, and LPL. Based on the results of the preliminary toxicity study, 75 and 150 mg/kg, twice daily doses of 18KHT01 were administered to evaluate anti-obesity activity in diet-induced obese (DIO) C57BL/6J mice model. The major obesity-related parameters such as body weight, weight gain, food efficiency ratio, as well as serum lipid profile were significantly reduced by 18KHT01 with potential synergism. Also, the high-fat diet-induced insulin resistance was suggestively alleviated by the formulation, and thus ameliorated fasting blood glucose. Histological evaluation of liver and white adipose tissue revealed that the significant reduction of fat depositions and thus reduction of these tissue weights. Synergy evaluation experiments exhibited that the 18KHT01 offered strong synergism by improving efficacy and reducing the toxicity of its ingredients. Overall results evidenced the 18KHT01 as a safe and potent anti-obesity herbal therapy.

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia–reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia–reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired.

Susceptibility to obesity changes during the course of life. We utilized the C57BL/6J (B6) and 129S mouse as a genetic model for variation in diet‐induced obesity to define the adiposity phenotypes from birth to maturity at 8 weeks‐of‐age. From birth to 8 weeks‐of‐age, both male and female 129S mice had significantly higher fat mass and adiposity index than B6 mice, although they were not obese. After 8 weeks‐of‐age, B6 had greater adiposity/obesity than 129S mice in response to a high fat (HF). We sought to determine the mechanism activating the fat accumulation in B6 mice at 8‐weeks‐of‐age. We used microarray analysis of gene expression during development of inguinal fat to show that molecular networks of lipogenesis were maximally expressed at 8 weeks‐of‐age. In addition, the DNA methylation analysis of the Sfrp5 promoter and binding of acetylated histones to Sfrp5 and Acly promoter regions showed that major differences in the expression of genes of lipogenesis and chromatin structure occur during development. Differences in lipogenesis networks could account for the strain‐dependent differences in adiposity up to 8 weeks‐of‐age; however, changes in the expression of genes in these networks were not associated with the susceptibility to DIO in B6 male mice beyond 8 weeks‐of‐age. Genetic variation of diet‐induced obesity between C57BL/6J (B6) and 129S mice depends on developmental age. Under an obesogenic diet, B6 mice did not develop obesity until they were 8 weeks‐of‐age. The genes and molecular networks of lipogenesis contribute to excessive lipid accumulation in fat depots of B6 mice at age weeks of age. Changes in the expression of these genes and their chromatin structures also followed development, but the latter were not tightly associated with variation in obesity between mouse strains.

Altering the balance between energy intake and expenditure is a major strategy for treating obesity. Nonetheless, despite the progression in antiobesity drugs on appetite suppression, therapies aimed at increasing energy expenditure are limited. Here, knockout ofAKAP1, a signaling hub on outer mitochondrial membrane, renders mice resistant to diet‐induced obesity.AKAP1 knockout significantly enhances energy expenditure and thermogenesis in brown adipose tissues (BATs) of obese mice. Restoring AKAP1 expression in BAT clearly reverses the beneficial antiobesity effect in AKAP1−/− mice. Mechanistically, AKAP1 remarkably decreases fatty acid β‐oxidation (FAO) by phosphorylating ACSL1 to inhibit its activity in a protein‐kinase‐A‐dependent manner and thus inhibits thermogenesis in brown adipocytes. Importantly, AKAP1 peptide inhibitor effectively alleviates diet‐induced obesity and insulin resistance. Altogether, the findings demonstrate that AKAP1 functions as a brake of FAO to promote diet‐induced obesity, which may be used as a potential therapeutic target for obesity. In high‐fat‐diet‐treated mice, A kinase anchoring protein 1 (AKAP1) functions as a brake molecule of fatty acid β‐oxidation by recruiting protein kinase A (PKA) and acyl‐CoA synthetase long chain family member 1 (ACSL1) to the outer mitochondrial membrane and inhibiting mitochondrial ACSL1 activity through PKA. AKAP1 elimination enhances mitochondrial ACSL1 activity and increases brown adipose thermogenesis, preventing mice from obesity.

Obesity is a multifactorial disease that is part of today's epidemic and also increases the risk of other metabolic diseases. Long noncoding RNAs (lncRNAs) provide one tier of regulatory mechanisms to maintain metabolic homeostasis. Although lncRNAs are a significant constituent of the mammalian genome, studies aimed at their metabolic significance, including obesity, are only beginning to be addressed. Here, a developmentally regulated lncRNA, termed as obesity related (Obr), whose expression in metabolically relevant tissues such as skeletal muscle, liver, and pancreas is altered in diet‐induced obesity, is identified. The Clone 9 cell line and high‐fat diet‐induced obese Wistar rats are used as a model system to verify the function of Obr. By using stable expression and antisense oligonucleotide‐mediated downregulation of the expression of Obr followed by different molecular biology experiments, its role in lipid metabolism is verified. It is shown that Obr associates with the cAMP response element‐binding protein (Creb) and activates different transcription factors involved in lipid metabolism. Its association with the Creb histone acetyltransferase complex, which includes the cAMP response element‐binding protein (CBP) and p300, positively regulates the transcription of genes involved in lipid metabolism. In addition, Obr is regulated by Pparγ in response to lipid accumulation. The long non‐coding RNA obesity‐related (Obr) promotes H3K27 acetylation and transcriptional upregulation of genes involved in lipid metabolism through its association with the Creb histone acetyltransferase complex, which includes the cAMP response element‐binding protein (Creb), CREB‐binding protein (Cbp), and p300. Obr is regulated by Peroxisome proliferator‐activated receptor gamma (Pparγ) in response to lipid levels from the HFD or other sources.

Aims/Introduction Peripheral neuropathy is a common complication of diabetes and also occurs in 30% of human obese individuals with impaired glucose tolerance. Even though peripheral neuropathy affects both sexes, most pre‐clinical studies have been carried out using male rodents. The aim of the present study was to create diet‐induced obesity and type 2 diabetes in female rats and mice in order to examine the development of peripheral neuropathy. Materials and Methods At 12 weeks‐of‐age, rats and mice were separated into three groups. Two groups or rats and mice were fed a 60‐kcal% high‐fat diet for 12 weeks (rats) or 8 weeks (mice). To induce type 2 diabetes, one group of high‐fat diet‐fed rats and mice were treated with a low dose of streptozotocin. Analyses of multiple neural end‐points were carried out 12 weeks later. Results Glucose utilization was impaired in diet‐induced obese female rats and mice, as was a number of neurological end‐points including nerve conduction velocity, intraepidermal and subepithelial corneal nerve fiber densities, and thermal and mechanical sensitivity. When female diet‐induced obese rats or mice were made hyperglycemic, glucose utilization and sensory nerve density of the skin and cornea, as well as thermal and mechanical sensitivity, were more significantly impaired compared with diet‐induced obese female rodents. Conclusions These studies show that diet‐induced obese and type 2 diabetic female rodents develop peripheral neuropathy that is similar to that occurring in male rodents. However, for female rats, more aggressive treatment is required to induce dietary obesity. Even though peripheral neuropathy affects both genders most pre‐clinical studies have been performed with only male rodents. The purpose of this study was to create diet induced obesity and type 2 diabetes in female rats and mice in order to examine development of peripheral neuropathy. The results from this study demonstrated that female rodents develop peripheral neuropathy.

A healthy skeletal muscle mass is essential in attenuating the complications of obesity. Importantly, healthy muscle function is maintained through adequate repair following overuse and injury. The purpose of this study was to investigate the impact of diet‐induced obesity (DIO) on skeletal muscle repair and the functionality of the muscle satellite cell (SC) population. Male C57BL/6J mice were fed a standard chow or high‐fat diet (60% kcal fat; DIO) for 8 weeks. Muscles from DIO mice subjected to cardiotoxin injury displayed attenuated muscle regeneration, as indicated by prolonged necrosis, delayed expression of MyoD and Myogenin, elevated collagen content, and persistent embryonic myosin heavy chain expression. While no significant differences in SC content were observed, SCs from DIO muscles did not activate normally nor did they respond to exogenous hepatocyte growth factor (HGF) despite similar receptor (cMet) density. Furthermore, HGF release from crushed muscle was significantly less than that from muscles of chow fed mice. This study demonstrates that deficits in muscle repair are present in DIO, and the impairments in the functionality of the muscle SC population as a result of altered HGF/c‐met signaling are contributors to the delayed regeneration. Here we demonstrate that skeletal muscle repair is attenuated with Diet‐Induced Obesity (DIO) and is characterized by persistent necrosis and delayed muscle regeneration. DIO muscles display a reduced quantity of hepatocyte growth factor (HGF) in response to crush injury. Even when Satellite Cells (SCs) derived from DIO muscles were incubated with a high dose of HGF, activation was significantly blunted compared to control fed mice suggesting an intrinsic defect within the SCs themselves. These data suggest that diet induced obesity leads to an attenuated regenerative capacity of skeletal muscle that can be accounted for, in part, by impaired satellite cell activation as a result of altered HGF signalling.

Obesity rates continue to rise in an unprecedented manner in what could be the most rapid population‐scale shift in human phenotype ever to occur. Increased consumption of unhealthy, calorie‐dense foods, coupled with sedentary lifestyles, is the main factor contributing to a positive energy balance and the development of obesity. Leptin and insulin are key hormones implicated in pathogenesis of this disorder and are crucial for controlling whole‐body energy homeostasis. Their respective function is mediated by the counterbalance of anorexigenic and orexigenic neurons located within the hypothalamic arcuate nucleus. Dysregulation of leptin and insulin signaling pathways within this brain region may contribute not only to the development of obesity, but also systemically affect the peripheral organs, thereby manifesting as metabolic diseases. Although the exact mechanisms detailing how these hypothalamic nuclei contribute to disease pathology are still unclear, increasing evidence suggests that altered DNA methylation may be involved. This review evaluates animal studies that have demonstrated diet‐induced DNA methylation changes in genes that regulate energy homeostasis within the arcuate nucleus, and elucidates possible mechanisms causing hypothalamic leptin and insulin resistance leading to the development of obesity and metabolic diseases. Arcuate nucleus dysregulation of leptin and insulin signaling contributes to the development of obesity. DNA methylation is influenced by environmental factors such as diet and is associated with several disease pathologies. Diet‐induced hypermethylation of important transcription factor binding sites reduces POMC expression, thereby affecting both leptin and insulin action. With POMC‐mediated leptin and insulin function playing a major role in the pathological development of obesity and metabolic diseases, the methylation status of POMC thus represents a pivotal therapeutic target.