Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs

The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.     

An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions

Obesity has become a global epidemic that has a negative impact on population health and the economy of nations. Genetic predispositions have been demonstrated to have a substantial role in the unbalanced energy metabolism seen in obesity. However, these genetic variations cannot entirely explain the massive growth in obesity over the last few decades. Accumulating evidence suggests that modern lifestyle characteristics such as the intake of energy-dense foods, adopting sedentary behavior, or exposure to environmental factors such as industrial endocrine disruptors all contribute to the rising obesity epidemic. Recent advances in the study of DNA and its alterations have considerably increased our understanding of the function of epigenetics in regulating energy metabolism and expenditure in obesity and metabolic diseases. These epigenetic modifications influence how DNA is transcribed without altering its sequence. They are dynamic, reflecting the interplay between the body and its surroundings. Notably, these epigenetic changes are reversible, making them appealing targets for therapeutic and corrective interventions. In this review, I discuss how these epigenetic modifications contribute to the disordered energy metabolism in obesity and to what degree lifestyle and weight reduction strategies and pharmacological drugs can restore energy balance by restoring normal epigenetic profiles.     

Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequelae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.     

Beneficial effects of vaccenic acid on postprandial lipid metabolism and dyslipidemia: Impact of natural trans‐fats to improve CVD risk

Abnormal non‐fasting (postprandial) lipid metabolism has been recognized as a significant contributor to dyslipidemia and cardiovascular disease (CVD) risk. Clinically, impaired metabolism of lipoproteins following a meal (e.g. chylomicrons) has been demonstrated in a number of chronic diseases, including obesity, insulin resistance, as well as type 1 and 2 diabetes. Given the proposed effects of dietary trans fat to contribute to a lipid profile that increases CVD risk, there has been a public health campaign in many countries to eliminate these fatty acids from the food supply. In contrast, our group has recently reported novel lipid‐lowering benefits of a major naturally‐occurring trans fatty acid vaccenic acid (VA, shorthand lipid name 18:1 trans‐11), in an animal model of dyslipidemia and the metabolic syndrome. Studies to date have shown that dietary supplementation of VA effectively reduces not only fasting lipids, but also postprandial triacylglycerol and chylomicron concentrations in obese JCR:LA‐cp rats. Evidence from animal studies to date suggest that VA may down‐regulate hepatic fatty acid synthesis and directly influence lipogenesis in the intestine. The discovery of new bioactive properties of VA is supported by clinical studies which have provided increased momentum for industry applications. In this review we summarize the emerging beneficial view of natural trans fats that have distinct and differential properties compared to those synthetically produced in partially hydrogenated vegetable oils (PHVO), with a particular focus on fasting and postprandial lipid metabolism in CVD risk.     

ASC Regulates Subcutaneous Adipose Tissue Lipogenesis and Lipolysis via p53/AMPKα Axis

Obesity has become an extensive threat to human health due to associated chronic inflammation and metabolic diseases. Apoptosis-associated speck-like protein (ASC) is a critical link between inflammasome and apoptosis-inducing proteins. In this study, we aimed to clarify the role of ASC in lipid metabolism. With high-fat diet (HFD) and knockout leptin gene mice (ob/ob), we found that ASC expression in subcutaneous adipose tissue (SAT) correlated with obesity. It could also positively regulate the reprogramming of cellular energy metabolism. Stromal vascular fractions (SVF) cells derived from the SAT of Asc^−/− mice or SVF from wild-type (WT) mice transfected with ASC siRNA were used to further investigate the underlying molecular mechanisms. We found ASC deficiency could lead to lipogenesis and inhibit lipolysis in SAT, aggravating lipid accumulation and impairing metabolic balance. In addition, our results showed that p53 and AMPKα expression were inhibited in SAT when ASC level was low. p53 and AMP-activated protein kinase α (AMPKα) were then assessed to elucidate whether they were downstream of ASC in regulating lipid metabolism. Our results revealed that ASC deficiency could promote lipid accumulation by increasing lipogenesis and decreasing lipolysis through p53/AMPKα axis. Regulation of ASC on lipid metabolism might be a novel therapeutic target for obesity.     

Curcumin and Weight Loss: Does It Work?

Obesity is a global health problem needing urgent research. Synthetic anti-obesity drugs show side effects and variable effectiveness. Thus, there is a tendency to use natural compounds for the management of obesity. There is a considerable body of knowledge, supported by rigorous experimental data, that natural polyphenols, including curcumin, can be an effective and safer alternative for managing obesity. Curcumin is a is an important compound present in Curcuma longa L. rhizome. It is a lipophilic molecule that rapidly permeates cell membrane. Curcumin has been used as a pharmacological traditional medicinal agent in Ayurvedic medicine for ∼6000 years. This plant metabolite doubtless effectiveness has been reported through increasingly detailed in vitro, in vivo and clinical trials. Regarding its biological effects, multiple health-promoting, disease-preventing and even treatment attributes have been remarkably highlighted. This review documents the status of research on anti-obesity mechanisms and evaluates the effectiveness of curcumin for management of obesity. It summarizes different mechanisms of anti-obesity action, associated with the enzymes, energy expenditure, adipocyte differentiation, lipid metabolism, gut microbiota and anti-inflammatory potential of curcumin. However, there is still a need for systematic and targeted clinical studies before curcumin can be used as the mainstream therapy for managing obesity.     

Obesity and Male Reproduction: Do Sirtuins Play a Role?

Obesity is a major current public health problem of global significance. A progressive sperm quality decline, and a decline in male fertility, have been reported in recent decades. Several studies have reported a strict relationship between obesity and male reproductive dysfunction. Among the many mechanisms by which obesity impairs male gonadal function, sirtuins (SIRTs) have an emerging role. SIRTs are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that play a role in gene regulation, metabolism, aging, and cancer. SIRTs regulate the energy balance, the lipid balance, glucose metabolism, and adipogenesis, but current evidence also indicates a role for SIRTs in male reproduction. However, the majority of the studies have been conducted in animal models and very few have been conducted with humans. This review shows that SIRTs play an important role among the molecular mechanisms by which obesity interferes with male fertility. This highlights the need to deepen this relationship. It will be of particular interest to evaluate whether synthetic and/or natural compounds capable of modifying the activity of SIRTs may also be useful for the treatment of obesity and its effects on gonadal function. Although few studies have explored the role of SIRT activators in obesity-induced male infertility, some molecules, such as resveratrol, appear to be effective in modulating SIRT activity, as well as counteracting the negative effects of obesity on male fertility. The search for strategies to improve male reproductive function in overweight/obese patients is a challenge and understanding the role of SIRTs and their activators may open new interesting scenarios in the coming years.     

Boesenbergia pandurata Attenuates Diet-Induced Obesity by Activating AMP-Activated Protein Kinase and Regulating Lipid Metabolism

Obesity, a chronic metabolic disorder, is characterized by enlarged fat mass and dysregulation of lipid metabolism. The medicinal plant, Boesenbergia pandurata (Roxb.) Schltr., has been reported to possess anti-oxidative and anti-inflammatory properties; however, its anti-obesity activity is unexplored. The present study was conducted to determine whether B. pandurata extract (BPE), prepared from its rhizome parts, attenuated high-fat diet (HFD)-induced obesity in C57BL/6J mice. The molecular mechanism was investigated in 3T3-L1 adipocytes and HepG2 human hepatoma cells. BPE treatment decreased triglyceride accumulation in both 3T3-L1 adipocytes and HepG2 hepatocytes by activating AMP-activated protein kinase (AMPK) signaling and regulating the expression of lipid metabolism-related proteins. In the animal model, oral administration of BPE (200 mg/kg/day for 8 weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were suppressed by BPE administration. Fat pad masses were reduced in BPE-treated mice, as evidenced by reduced adipocyte size. Furthermore, BPE protected against the development of nonalcoholic fatty liver by decreasing hepatic triglyceride accumulation. BPE also activated AMPK signaling and altered the expression of lipid metabolism-related proteins in white adipose tissue and liver. Taken together, these findings indicate that BPE attenuates HFD-induced obesity by activating AMPK and regulating lipid metabolism, suggesting a potent anti-obesity agent.     

Lactiplantibacillusplantarum ATG-K2 Exerts an Anti-Obesity Effect in High-Fat Diet-Induced Obese Mice by Modulating the Gut Microbiome

Obesity is a major health problem. Compelling evidence supports the beneficial effects of probiotics on obesity. However, the anti-obesity effect of probiotics remains unknown. In this study, we investigated the anti-obesity effects and potential mechanisms of Lactiplantibacillus plantarum ATG-K2 using 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. 3T3-L1 cells were incubated to determine the effect of lipid accumulation with lysate of L. plantarum ATG-K2. Mice were fed a normal fat diet or HFD with L. plantarum ATG-K2 and Orlistat for 8 weeks. L. plantarum ATG-K2 inhibited lipid accumulation in 3T3-L1 adipocytes, and reduced body weight gain, WAT weight, and adipocyte size in HFD-induced obese mice, concurrently with the downregulation of PPARγ, SREBP1c, and FAS and upregulation of PPARα, CTP1, UCP1, Prdm16, and ND5. Moreover, L. plantarum ATG-K2 decreased TG, T-CHO, leptin, and TNF-α levels in the serum, with corresponding gene expression levels in the intestine. L. plantarum ATG-K2 modulated the gut microbiome by increasing the abundance of the Lactobacillaceae family, which increased SCFA levels and branched SCFAs in the feces. L. plantarum ATG-K2 exhibited an anti-obesity effect and anti-hyperlipidemic effect in 3T3-L1 adipocytes and HFD-induced obese mice by alleviating the inflammatory response and regulating lipid metabolism, which may be influenced by modulation of the gut microbiome and its metabolites. Therefore, L. plantarum ATG-K2 can be a preventive and therapeutic agent for obesity.     

The Immune Response in Adipocytes and Their Susceptibility to Infection: A Possible Relationship with Infectobesity

The current obesity pandemic has been expanding in both developing and developed countries. This suggests that the factors contributing to this condition need to be reconsidered since some new factors are arising as etiological causes of this disease. Moreover, recent clinical and experimental findings have shown an association between the progress of obesity and some infections, and the functions of adipose tissues, which involve cell metabolism and adipokine release, among others. Furthermore, it has recently been reported that adipocytes could either be reservoirs for these pathogens or play an active role in this process. In addition, there is abundant evidence indicating that during obesity, the immune system is exacerbated, suggesting an increased susceptibility of the patient to the development of several forms of illness or death. Thus, there could be a relationship between infection as a trigger for an increase in adipose cells and the impact on the metabolism that contributes to the development of obesity. In this review, we describe the findings concerning the role of adipose tissue as a mediator in the immune response as well as the possible role of adipocytes as infection targets, with both roles constituting a possible cause of obesity.     

The Role of Molecular and Hormonal Factors in Obesity and the Effects of Physical Activity in Children

Obesity and overweight are defined as abnormal fat accumulations. Adipose tissue consists of more than merely adipocytes; each adipocyte is closely coupled with the extracellular matrix. Adipose tissue stores excess energy through expansion. Obesity is caused by the abnormal expansion of adipose tissue as a result of adipocyte hypertrophy and hyperplasia. The process of obesity is controlled by several molecules, such as integrins, kindlins, or matrix metalloproteinases. In children with obesity, metabolomics studies have provided insight into the existence of unique metabolic profiles. As a result of low-grade inflammation in the system, abnormalities were observed in several metabolites associated with lipid, carbohydrate, and amino acid pathways. In addition, obesity and related hormones, such as leptin, play an instrumental role in regulating food intake and contributing to childhood obesity. The World Health Organization states that physical activity benefits the heart, the body, and the mind. Several noncommunicable diseases, such as cardiovascular disease, cancer, and diabetes, can be prevented and managed through physical activity. In this work, we reviewed pediatric studies that examined the molecular and hormonal control of obesity and the influence of physical activity on children with obesity or overweight. The purpose of this review was to examine some orchestrators involved in this disease and how they are related to pediatric populations. A larger number of randomized clinical trials with larger sample sizes and long-term studies could lead to the discovery of new key molecules as well as the detection of significant factors in the coming years. In order to improve the health of the pediatric population, omics analyses and machine learning techniques can be combined in order to improve treatment decisions.     

Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.     

Vitamin D: Link between Osteoporosis,Obesity, and Diabetes?

Vitamin D (1,25(OH)₂D₃) is a steroid hormone that has a range of physiological functions in skeletal and nonskeletal tissues, and can contribute to prevent and/or treat osteoporosis, obesity, and Type 2 diabetes mellitus (T2DM). In bone metabolism, vitamin D increases the plasma levels of calcium and phosphorus, regulates osteoblast and osteoclast the activity, and combats PTH hypersecretion, promoting bone formation and preventing/treating osteoporosis. This evidence is supported by most clinical studies, especially those that have included calcium and assessed the effects of vitamin D doses (≥800 IU/day) on bone mineral density. However, annual megadoses should be avoided as they impair bone health. Recent findings suggest that low serum vitamin D is the consequence (not the cause) of obesity and the results from randomized double-blind clinical trials are still scarce and inconclusive to establish the relationship between vitamin D, obesity, and T2DM. Nevertheless, there is evidence that vitamin D inhibits fat accumulation, increases insulin synthesis and preserves pancreatic islet cells, decreases insulin resistance and reduces hunger, favoring obesity and T2DM control. To date, there is not enough scientific evidence to support the use of vitamin D as a pathway to prevent and/or treat obesity and T2DM.     

ATP-Binding Cassette Protein ABCC10 Deficiency Prevents Diet-Induced Obesity but Not Atherosclerosis in Mice

Excess plasma lipid levels are a risk factor for various cardiometabolic disorders. Studies have shown that improving dyslipidemia lowers the progression of these disorders. In this study, we investigated the role of ATP-binding cassette transporter C10 (ABCC10) in regulating lipid metabolism. Our data indicate that deletion of the Abcc10 gene in male mice results in lower plasma and intestinal triglycerides by around 38% and 36%, respectively. Furthermore, deletion of ABCC10 ameliorates diet-induced obesity in mice and leads to a better response during insulin and glucose tolerance tests. Unexpectedly, ABCC10 deficiency does not affect triglyceride levels or atherosclerosis in ApoE-deficient mice. In addition, our studies demonstrate low oleate uptake by enterocytes (~25–30%) and less absorption (~37%) of triglycerides in the small intestine of ABCC10 knockout mice. Deletion of the Abcc10 gene also alters several lipid metabolism genes in the intestine, suggesting that ABCC10 regulates dietary fat absorption, which may contribute to diet-induced obesity in mice.     

Melatonin in Early Nutrition: Long-Term Effects on Cardiovascular System

Breastfeeding protects against adverse cardiovascular outcomes in the long term. Melatonin is an active molecule that is present in the breast milk produced at night beginning in the first stages of lactation. This indoleamine appears to be a relevant contributor to the benefits of breast milk because it can affect infant health in several ways. The melatonin concentration in breast milk varies in a circadian pattern, making breast milk a chrononutrient. The consumption of melatonin can induce the first circadian stimulation in the infant’s body at an age when his/her own circadian machinery is not functioning yet. This molecule is also a powerful antioxidant with the ability to act on infant cells directly as a scavenger and indirectly by lowering oxidant molecule production and enhancing the antioxidant capacity of the body. Melatonin also participates in regulating inflammation. Furthermore, melatonin can participate in shaping the gut microbiota composition, richness, and variation over time, also modulating which molecules are absorbed by the host. In all these ways, melatonin from breast milk influences weight gain in infants, limiting the development of obesity and comorbidities in the long term, and it can help shape the ideal cellular environment for the development of the infant’s cardiovascular system.     

Clinical Evidence on the Potential Beneficial Effects of Probiotics and Prebiotics in Cardiovascular Disease

The ‘gut microbiome’—the hundreds of trillions of bacteria in the human gastrointestinal tract—serves several functions. The gut microbiome includes all the microorganisms, bacteria, viruses, protozoa, and fungi in the gastrointestinal tract and their genetic material. It helps digest indigestible foods and produces nutrients. Through the metabolism of sugars and proteins, it helps the intestinal barrier, the immune system, and metabolism. Some bacteria, such as those in the gut microbiome, cause disease, but others are essential to our health. These “good” microbes protect us from pathogens. Numerous studies have linked an unhealthy gut microbiome to obesity, insulin resistance, depression, and cardiometabolic risk factors. To maximize probiotic benefits in each case, knowledge of probiotic bacterial strains and how to consume them should be increased. This study aims to examine the benefits of probiotic and prebiotic organisms on cardiovascular health, specifically on heart disease, coronary heart disease, stroke, and hypertension. To complete the research, a literature review was conducted by gathering clinical studies and data. The clinical evidence demonstrates the beneficial effect of probiotics and prebiotic microorganisms on the gut microbiome, which has multiple benefits for overall health and especially for cardiovascular diseases.     

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis

Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis.     

Use of Melatonin in Cancer Treatment: Where Are We?

Cancer represents a large group of diseases accounting for nearly 10 million deaths each year. Various treatment strategies, including surgical resection combined with chemotherapy, radiotherapy, and immunotherapy, have been applied for cancer treatment. However, the outcomes remain largely unsatisfying. Melatonin, as an endogenous hormone, is associated with the circadian rhythm moderation. Many physiological functions of melatonin besides sleep–wake cycle control have been identified, such as antioxidant, immunomodulation, and anti-inflammation. In recent years, an increasing number of studies have described the anticancer effects of melatonin. This has drawn our attention to the potential usage of melatonin for cancer treatment in the clinical setting, although huge obstacles still exist before its wide clinical administration is accepted. The exact mechanisms behind its anticancer effects remain unclear, and the specific characters impede its in vivo investigation. In this review, we will summarize the latest advances in melatonin studies, including its chemical properties, the possible mechanisms for its anticancer effects, and the ongoing clinical trials. Importantly, challenges for the clinical application of melatonin will be discussed, accompanied with our perspectives on its future development. Finally, obstacles and perspectives of using melatonin for cancer treatment will be proposed. The present article will provide a comprehensive foundation for applying melatonin as a preventive and therapeutic agent for cancer treatment.