Modelling molecular processes in weight loss:Regulation of metabolic flexibility

The World Health Organisation has estimated a three-fold increase in global obesity from 1975 to 2018. This is alarming as obesity is associated with several chronic illnesses including cardiovascular diseases, type 2 diabetes, metabolic syndrome, and several forms of cancer. This research utilises multiple types of data from a weight loss study to identify key cellular processes in the cells of the adipose tissue involved in weight loss. The objective is to highlight cellular pathways and genes, which can be targeted to counter obesity and associated illnesses. It was observed that metabolic flexibility, the ability of organisms to switch between metabolic nutrients, was impaired in obese individuals along with an increase in inflammation, indicating possible interactions between the two leading to the development of chronic illnesses in obesity

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high‐fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high‐fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age‐related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bruce Keller, Annadora J.. State University of Louisiana; Estados UnidosFil: Morrison, Christopher D.. State University of Louisiana; Estados UnidosFil: Fernandez Kim, Sun Ok. State University of Louisiana; Estados UnidosFil: Ebenezer, Philip J.. State University of Louisiana; Estados UnidosFil: Zhang, Le. State University of Louisiana; Estados UnidosFil: Dasuri, Kalavathi. State University of Louisiana; Estados UnidosFil: Keller, Jeffrey N.. State University of Louisiana; Estados Unido

Caffeine with Links to NAFLD and Accelerated Brain Aging

Nutritional diets are essential to prevent nonalcoholic fatty liver disease (NAFLD) in the global obesity and diabetes epidemic. The ingestion of palmitic acid-rich diets induces NAFLD in animal and human studies. The beneficial properties of olive oil (oleic acid) may be superseded by ingestion of palmitic acid-rich diets. Hepatic caffeine metabolism is regulated by palmitic and oleic acid with effects of these fats on amyloid beta metabolism. Healthy fats such as olive oil may facilitate rapid amyloid beta clearance in the periphery to maintain drug therapy in diabetes and various neurological diseases. Repression of the anti-aging gene sirtuin 1 (Sirt 1) prevents the beneficial properties of olive oil. Brain disorders induce NAFLD and supersede caffeine’s therapeutic effects in the prevention of NAFLD. Delayed hepatic caffeine metabolism in NAFLD and increased caffeine transport to the brain with aging-induced mitophagy in neurons with induction of type 3 diabetes and neurodegenerative disease

Fat-specific Dicer Deficiency Accelerates Aging And Mitigates Several Effects Of Dietary Restriction In Mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branchedchain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.8120112222010/52557-0, FAPESP, Fundação de Amparo à Pesquisa do Estado de São PauloFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

The interplay between obesity and cancer: a fly view

Accumulating epidemiological evidence indicates a strong clinical association between obesity and an increased risk of cancer. The global pandemic of obesity indicates a public health trend towards a substantial increase in cancer incidence and mortality. However, the mechanisms that link obesity to cancer remain incompletely understood. The fruit fly Drosophila melanogaster has been increasingly used to model an expanding spectrum of human diseases. Fly models provide a genetically simpler system that is ideal for use as a first step towards dissecting disease interactions. Recently, the combining of fly models of diet-induced obesity with models of cancer has provided a novel model system in which to study the biological mechanisms that underlie the connections between obesity and cancer. In this Review, I summarize recent advances, made using Drosophila, in our understanding of the interplay between diet, obesity, insulin resistance and cancer. I also discuss how the biological mechanisms and therapeutic targets that have been identified in fly studies could be utilized to develop preventative interventions and treatment strategies for obesityassociated cancers

Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development.

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators

Interplay between genetic predisposition and diet in advancing obesity and type 2 Diabetes in the Tallyho mouse

Obesity is a global epidemic, affecting all ages. It is one of the leading causes of preventable death, as it increases the risk of type 2 diabetes (T2D), hypertension, cardiovascular disease, nonalcoholic fatty liver disease, and some cancers. Obesity is a complex disease that is caused by a combination of genetic and environmental factors such as diets high in fat and sedentary life style. Despite our increased knowledge of obesity development and progression, current obesity treatments have not stopped the rise in obesity rates. There are still many unknowns related to the underlying mechanisms of obesity that need to be investigated and understood, so that treatment of obesity can be more effective. To deal with the numerous variables involved with such studies, animal models are recommended. My dissertation centers around characterizing the TALLYHO/Jng (TH) mouse, a polygenic model for T2D and obesity, and identifying obesity gene(s) in this model. The first study focused on investigating the effect of diets high in fat and sucrose for the development of obesity and T2D in TH mice. Compared to normal C57BL/6J (B6) mice, TH mice responded more sensitively to the obesogenic diets in the development of obesity and type 2 diabetes, demonstrating that diets are important modulators of genetic susceptibility to the diseases in this model. The second study was conducted in an effort to identify obesity gene(s) in TH mice. We generated congenic mouse strains carrying obesity quantitative trait loci on chromosome 1 derived from TH mice on B6 background. Using these mouse strains, we determined that the distal segment of chromosome 1 from TH mice is necessary to cause diet induced obesity. In the last study, we demonstrated that increased pro-inflammatory cytokine interleukin-6 levels and decreased mitochondrial respiration may be in part a mechanism underlying the gene-diet interaction in advancing obesity and type 2 diabetes in TH mice

A data-driven computational model for obesity-driven diabetes onset and remission through weight loss

Obesity is a major risk factor for the development of type 2 diabetes (T2D), where a sustained weight loss may result in T2D remission in individuals with obesity. To design effective and feasible intervention strategies to prevent or reverse T2D, it is imperative to study the progression of T2D and remission together. Unfortunately, this is not possible through experimental and observational studies. To address this issue, we introduce a data-driven computational model and use human data to investigate the progression of T2D with obesity and remission through weight loss on the same timeline. We identify thresholds for the emergence of T2D and necessary conditions for remission. We explain why remission is only possible within a window of opportunity and the way that window depends on the progression history of T2D, individual’s metabolic state, and calorie restrictions. These findings can help to optimize therapeutic intervention strategies for T2D prevention or treatment