Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.
Aging ; Brain/metabolism* ; Energy Metabolism ; Humans ; Hypothalamus/metabolism* ; Obesity/metabolism*

BACKGROUND: Various methods and equations are available to predict the basal metabolic rate (BMR). A published study comparing the Harris-Benedict Equation, Bioelectrical Impedance Analysis, and Indirect Calorimetry (IC), was done among Filipinos, and was able to obtain a novel formula for BMR. The purpose of this study is to validate this novel formula. METHODS: This is a multi-center, cross-sectional, validation study of the novel BMR equation, done among adult overweight and obese Filipinos, who were seen at St. Luke’s Medical Center and Providence Hospital in Quezon City, Outpatient Clinics from August 2019 to March 2020. Purposive sampling was done, and upon giving consent, subjects had undergone interview, anthropometrics measurement, and IC. RESULTS: 174 samples were enrolled. Mean age is 43 years old, majority are females. 27% have no co-morbidities; of those with co-morbidities, half have diabetes mellitus (DM). Mean weight is 74.30 kg; mean BMI is 29.78 kg/m2 . The mean computed BMR is 1174.70 kcal/day, which is 145.83 significantly lower than the BMR derived with calorimetry: 1320.53 kcal/day (P-value 0.000). However, the scatterplot reveals the linearity of positive direction for both values. 31% of the computed BMR fell within the +/-10% estimate of the actual BMR. Stratification of the results between those with DM and without, lowered the difference between the calculated and actual BMR to 46 kcal/day (from 145.83) among the DM subgroup, and increased the estimated accuracy to 38% falling within the +/- 10% estimate of the actual values. CONCLUSION: The novel BMR formula is linearly reflective of the basal metabolism of adult overweight and obese Filipinos, but the numerical values are lower compared to actual calorimetry results, yielding more accuracy when applied among patients with diabetes.
Calorimetry, Indirect ; Basal Metabolism ; Obesity Management

The purpose of this study was to assess the daily steps, physical activities and activity coefficient of the elementary school children in the rural area. Body weight, height and daily steps were measured and one-day activity diaries were collected by interviewing children. The average age of the subjects was 9.96+/-1.02 years. Average height, weight, obesity index, body fat and muscle of subjects were 136.2+/-8.9 cm, 35.2+/-8.5 kg, 99.6+/-18.8%, 22.9+/-8.5% and 35.8+/-6.0%, respectively. The average daily steps of the subjects was 17,584 and daily steps (19,314) of 3rd grade students was significantly higher than that (15,712) of 5th grade children. But there was no significant difference in daily steps and activity coefficients between boys and girls. Daily steps (23,347) of exercise group showed the significantly higher than that (16,144) of nonexercise group. Gender and grade of subjects did not have significant influence on activity coefficients, but there was a significant difference in activity coefficient on weekdays between the exercise group (1.82+/-0.30) and non-exercise group (1.50+/-0.21). Analysis of variance revealed stronger associations between daily steps and body fat (%) than between daily steps and BMI. Daily steps showed significant negative correlation with body fat (%) measured using two methods r =-0.321 and r = -0.365, respectively. Activity coefficient was significantly correlated (r = 0.436) with daily steps, thus increasing daily steps can prevent and treat childhood obesity by increasing the energy expenditure. The higher activity coefficients (weekday 1.56, weekend 1.53) of the subjects was caused by the fact that rural students spent more time outside and enjoyed stronger activities than urban students. The results of this study can be used to estimate energy requirements for Korean children based on exercise levels and living areas.
Adipose Tissue ; Body Weight ; Child* ; Energy Metabolism ; Female ; Humans ; Motor Activity* ; Obesity ; Pediatric Obesity

Increased intracellular levels of Ca²⁺ are generally thought to negatively regulate lipolysis in mature adipocytes, whereas store-operated Ca²⁺ entry was recently reported to facilitate lipolysis and attenuate lipotoxicity by inducing lipophagy. Transient receptor potential mucolipin1 (TRPML1), a Ca²⁺-permeable non-selective cation channel, is mainly expressed on the lysosomal membrane and plays key roles in lysosomal homeostasis and membrane trafficking. However, the roles of TRPML1 in lipolysis remains unclear. In this study, we examined whether the channel function of TRPML1 induces lipolysis in mature adipocytes. We found that treatment of mature adipocytes with ML-SA1, a specific agonist of TRPML1, solely upregulated extracellular glycerol release, but not to the same extent as isoproterenol. In addition, knockdown of TRPML1 in mature adipocytes significantly reduced autophagic flux, regardless of ML-SA1 treatment. Our findings demonstrate that the channel function of TRPML1 partially contributes to lipid metabolism and autophagic membrane trafficking, suggesting that TRPML1, particularly the channel function of TRPML1, is as therapeutic target molecule for treating obesity.
Adipocytes ; Glycerol ; Homeostasis ; Isoproterenol ; Lipid Metabolism ; Lipolysis ; Membranes ; Obesity

Oesity is a major global health problem. However, current therapeutic strategies for obesity are limited. Obesity results from an imbalance between energy intake and energy expenditure, and the treatment of obesity is based on the correction of this metabolic imbalance. Anti-obesity drugs can shift this balance in a favorable way by reducing food intake, altering metabolism, and by increasing energy expenditure. There is a growing consensus that pharmacotherapy is appropriate for many individuals who are unable to lose weight through less intensive measures. However, side effects may ensue phamacotherapy for obesity. Only two drugs (sibutramine and orlistat) are currently approved for the long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. Orlistat works by blocking the pancreatic lipase. However, phamarcotherapy may not be the ultimate resolution for obesity management. Because the underlying pathophysiology in each individual varies in many aspects, it is recommended to provide individualized and tailored medication in addition to other antiobesity supportive treatments.
Anti-Obesity Agents ; Consensus ; Drug Therapy ; Eating ; Energy Intake ; Energy Metabolism ; Health Expenditures ; Lipase ; Metabolism ; Norepinephrine ; Obesity* ; Serotonin

Insulin resistance is the pathophysiological hallmark of various kinds of clinical diseases, including non- alcoholic fatty liver disease. Insulin resistance is the common characteristic of metabolic syndrome and its related features. Insulin resistance is a systemic disease that affects the nervous system, muscles, pancreas, kidney, heart and immune system, in addition to the liver. A complex interaction between genes and environment factors enhances insulin resistance and the phenotypic expression of NAFLD (non- alcoholic fatty liver disease) in individual patients. Advanced fibrotic liver disease is associated with many features of metabolic syndrome, and the risk of progressive liver disease should not be underestimated for the individuals suffering with metabolic disorders. Abnormalities of insulin signaling can cause the state of insulin resistance, but there is no clear cut scientific evidence that distorted insulin signaling is the primary pathophysiological defect. Increased adipose tissue mass can cause peripheral tissue insulin resistance via the changes of the adipocytokine secretory patterns. We discuss in this article the sequences of the insulin signaling cascades and the possible molecular targets of insulin resistance, the humoral "cross talk" between the distorted secretory patterns of the adipocytokines, and the peripheral tissue insulin resistance along with the pathophysiology of NAFLD.
Signal Transduction ; Obesity/metabolism ; *Insulin Resistance ; Humans ; Fatty Liver/*metabolism ; Adipose Tissue/metabolism

Non-alcoholic fatty liver disease (NAFLD) is a metabolic-related disorder induced by multiple factors and mainly characterized by excessive fat buildup in hepatocytes. With the consumption of a Western-style diet and obesity prevalence in recent years, the incidence of NAFLD has gradually increased, becoming an increasingly serious public health problem. Bilirubin is a heme metabolite and a potent antioxidant. Studies have demonstrated that bilirubin levels have an inverse correlation with the incidence rate of NAFLD; however, which form of bilirubin plays the main protective role is still controversial. It is considered that the main protective mechanisms for NAFLD are bilirubin antioxidant properties, insulin resistance reduction, and mitochondrial function. This article summarizes the correlation, protective mechanism, and possible clinical application of NAFLD and bilirubin.
Humans ; Non-alcoholic Fatty Liver Disease/metabolism* ; Bilirubin ; Antioxidants ; Obesity/complications* ; Hepatocytes/metabolism* ; Liver/metabolism*

Insulin resistance is a major risk factor for developing type 2 diabetes caused by the inability of insulin-target tissues to respond properly to insulin, and contributes to the morbidity of obesity. Insulin action involves a series of signaling cascades initiated by insulin binding to its receptor, eliciting receptor autophosphorylation and activation of the receptor tyrosine kinase, resulting in tyrosine phosphorylation of insulin receptor substrates (IRSs). Phosphorylation of IRSs leads to activation of phosphatidylinositol 3-kinase (PI3K) and, subsequently, to activation of Akt and its downstream mediator AS160, all of which are important steps for stimulating glucose transport induced by insulin. Although the mechanisms underlying insulin resistance are not completely understood in skeletal muscle, it is thought to result, at least in part, from impaired insulin-dependent PI3K activation and downstream signaling. This review focuses on the molecular basis of skeletal muscle insulin resistance in obesity and type 2 diabetes. In addition, the effects of insulin-sensitizing agent treatment and lifestyle intervention of human insulin-resistant subjects on insulin signaling cascade are discussed. Furthermore, the role of Rho-kinase, a newly identified regulator of insulin action in insulin control of metabolism, is addressed.
Blood Glucose/*metabolism ; Diabetes Mellitus, Type 2/*metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/*physiology ; Obesity, Abdominal/*metabolism ; Signal Transduction/physiology

Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.
Animals ; Anti-Obesity Agents ; therapeutic use ; Cannabinoid Receptor Modulators ; antagonists & inhibitors ; metabolism ; Endocannabinoids ; Humans ; Obesity ; drug therapy ; metabolism ; Piperidines ; therapeutic use ; Pyrazoles ; therapeutic use ; Receptors, Cannabinoid ; metabolism

Adipose tissue is a highly heterogeneous endocrine organ. The heterogeneity among different anatomical depots stems from their intrinsic differences in cellular and physiological properties, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, insulin sensitivity, hormonal control, thermogenic ability and vascularization. Additional factors that influence adipose tissue heterogeneity are genetic predisposition, environment, gender and age. Under obese condition, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. For instance, individuals with central obesity are more susceptible to developing diabetes and cardiovascular complications, whereas those with peripheral obesity are more metabolically healthy. This review summarizes the clinical and mechanistic evidence for the depot-specific differences that give rise to different metabolic consequences, and provides therapeutic insights for targeted treatment of obesity.
Adipose Tissue ; Adipose Tissue, White* ; Genetic Predisposition to Disease ; Glucose ; Insulin Resistance ; Lipid Metabolism ; Obesity ; Obesity, Abdominal ; Population Characteristics*