The Circadian Clock of Müller Glia Is Necessary for Retinal Homeostasis and Neuronal Survival.

Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized.

From fasting to fat reshaping: exploring the molecular pathways of intermittent fasting-induced adipose tissue remodeling.

Obesity, characterised by excessive fat accumulation, is a complex chronic condition that results from dysfunctional adipose tissue expansion due to prolonged calorie surplus. This leads to rapid adipocyte enlargement that exceeds the support capacity of the surrounding neurovascular network, resulting in increased hypoxia, inflammation, and insulin resistance. Intermittent fasting (IF), a dietary regimen that cycles between periods of fasting and eating, has emerged as an effective strategy to combat obesity and improve metabolic homeostasis by promoting healthy adipose tissue remodeling.

Reprogramming of Energy Metabolism in Human Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation.

Lactate promotes fatty acid oxidation by the tricarboxylic acid cycle and mitochondrial respiration in muscles of obese mice.

Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism.

Obesity and the cerebral cortex: Underlying neurobiology in mice and humans.

Obesity is a major modifiable risk factor for Alzheimer's disease (AD), characterized by progressive atrophy of the cerebral cortex. The neurobiology of obesity contributions to AD is poorly understood. Here we show with in vivo MRI that diet-induced obesity decreases cortical volume in mice, and that higher body adiposity associates with lower cortical volume in humans.

Inhibitory Regulation of FOXO1 in PPARδ Expression Drives Mitochondrial Dysfunction and Insulin Resistance.

Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle-specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes.

Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue.

The aging of white adipose tissue (WAT) involves senescence of adipose stem and progenitor cells (ASPCs) and dysregulation of immune cell populations, serving as a major driver of age-associated adipose dysfunction and metabolic diseases. Conversely, the elimination of senescent ASPCs is associated with improvements in overall health. Intermittent fasting (IF), a dietary intervention that incorporates periodic cycles of fasting and refeeding, has been reported to promote weight loss and fat mass reduction and improve glucose and insulin homeostasis in both murine and human studies.

Immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells survive long term in allogeneic hosts.

The immunogenicity of transplanted allogeneic cells and tissues is a major hurdle to the advancement of cell therapies. Here we show that the overexpression of eight immunomodulatory transgenes (Pdl1, Cd200, Cd47, H2-M3, Fasl, Serpinb9, Ccl21 and Mfge8) in mouse embryonic stem cells (mESCs) is sufficient to immunologically 'cloak' the cells as well as tissues derived from them, allowing their survival for months in outbred and allogeneic inbred recipients. Overexpression of the human orthologues of these genes in human ESCs abolished the activation of allogeneic human peripheral blood mononuclear cells and their inflammatory responses.

Diet and Polycystic Kidney Disease: Nutrients, Foods, Dietary Patterns, and Implications for Practice.

Polycystic kidney disease (PKD) is a chronic, progressive hereditary condition characterized by abnormal development and growth of cysts in the kidneys and other organs. There is increasing interest in exploring whether dietary modifications may prevent or slow the disease course in people with PKD. Although vasopressin-receptor agonists have emerged as a novel drug treatment in advancing care for people with PKD, several recent landmark trials and clinical discoveries also have provided new insights into potential dietary-related therapeutic strategies.

Adipose Tissue and Plasma Markers Associated with HbA1c Pre- and Post-bariatric Surgery: a Cross-sectional and Cohort Study.

Purpose: Obesity can be associated with chronic inflammation and dysregulated expression of inflammatory adipokines that contribute to insulin resistance and type 2 diabetes. This may also affect the clinical response to bariatric surgery. Our objective was whether baseline visceral adipose tissue features and plasma adipokine are associated with HbA1c ≥0.

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs.

Gut microbiome modified by bariatric surgery improves insulin sensitivity and correlates with increased brown fat activity and energy expenditure.

Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice.

Disruption of adipocyte YAP improves glucose homeostasis in mice and decreases adipose tissue fibrosis.

Objective: Adipose tissue is a very dynamic metabolic organ that plays an essential role in regulating whole-body glucose homeostasis. Dysfunctional adipose tissue hypertrophy with obesity is associated with fibrosis and type 2 diabetes. Yes-associated protein 1 (YAP) is a transcription cofactor important in the Hippo signaling pathway.

Shared pathobiology identifies AMPK as a therapeutic target for obesity and autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression.

Circadian rhythms in metabolic organs and the microbiota during acute fasting in mice.

The circadian clock regulates metabolism in anticipation of regular changes in the environment. It is found throughout the body, including in key metabolic organs such as the liver, adipose tissues, and intestine, where the timing of the clock is set largely by nutrient signaling. However, the circadian clocks of these tissues during the fasted state have not been completely characterized.

Characterization of adipose depot-specific stromal cell populations by single-cell mass cytometry.

The increased prevalence of obesity and metabolic diseases has heightened interest in adipose tissue biology and its potential as a therapeutic target. To better understand cellular heterogeneity and complexity of white adipose tissue (WAT), we employed cytometry by time-of-flight (CyTOF) to characterize immune and stromal cells in visceral and subcutaneous WAT depots under normal and high-fat diet feeding, by quantifying the expression levels of 32 surface marker proteins. We observed comparable proportions of immune cells in two WAT depots under steady state, but depot-distinct subtypes of adipose precursor cells (APC), suggesting differences in their adipogenic and fibrogenic potential.

Nutritional Regulation of Mammary Tumor Microenvironment.

The mammary gland is a heterogeneous organ comprising of immune cells, surrounding adipose stromal cells, vascular cells, mammary epithelial, and cancer stem cells. In response to nutritional stimuli, dynamic interactions amongst these cell populations can be modulated, consequently leading to an alteration of the glandular function, physiology, and ultimately disease pathogenesis. For example, obesity, a chronic over-nutritional condition, is known to disrupt homeostasis within the mammary gland and increase risk of breast cancer development.

Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens, including caloric restriction, intermittent fasting, and ketogenic diets, hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited.

COVID-19 and obesity: fighting two pandemics with intermittent fasting.

Obesity is strongly and independently associated with an increased risk of severe illness and death from coronavirus disease 2019 (COVID-19). The pathophysiological changes that result from elevated body weight lead to metabolic dysfunction, chronic inflammation, impaired immunological responses, and multisystem disorders, which increase vulnerability to severe illness from COVID-19. While vaccination strategies are under way across the world, the second and third waves of the pandemic, along with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, continue to threaten the stability of medical systems worldwide.

VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.

Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction.

Physiological Responses of Post-Dietary Effects: Lessons from Pre-Clinical and Clinical Studies.

Dieting regimens such as calorie restriction (CR) are among the most commonly practiced interventions for weight management and metabolic abnormalities. Due to its independence from pharmacological agents and considerable flexibility in regimens, many individuals turn to dieting as a form of mitigation and maintenance of metabolic health. While metabolic benefits of CR have been widely studied, weight loss maintenance and metabolic benefits are reported to be lost overtime when the diet regimen has been terminated-referred to as post-dietary effects.

Feeding Rhythms and the Circadian Regulation of Metabolism.

The molecular circadian clock regulates metabolic processes within the cell, and the alignment of these clocks between tissues is essential for the maintenance of metabolic homeostasis. The possibility of misalignment arises from the differential responsiveness of tissues to the environmental cues that synchronize the clock (zeitgebers). Although light is the dominant environmental cue for the master clock of the suprachiasmatic nucleus, many other tissues are sensitive to feeding and fasting.

Intermittent Fasting: Physiological Implications on Outcomes in Mice and Men.

Intermittent fasting (IF) is a widely practiced dietary method that encompasses periodic restriction of food consumption. Due to its protective benefits against metabolic diseases, aging, and cardiovascular and neurodegenerative diseases, IF continues to gain attention as a preventative and therapeutic intervention to counteract these chronic diseases. Although numerous animal studies have reported positive health benefits of IF, its feasibility and efficacy in clinical settings remain controversial.