obesity

Effects of Apolipoprotein A4 on Lipid Metabolism via Sympathetic Regulation

Obesity increases the risks and progression of hypertriglyceridemia, metabolic dysfunction- associated steatotic liver disease (MASLD), and cardiovascular diseases. Previous studies demonstrate that a single injection of apolipoprotein A4 (APOA4) elevates sympathetic neural activity and fatty acid β-oxidation in adipose tissues; and consistent infusion of APOA4 in obese mice fed a high-fat diet lowers fat mass, reduces hypertriglyceridemia, elevates brown adipose tissue thermogenesis, and attenuates steatosis and enhances sympathetic neural activity in the liver. This project hypothesizes that APOA4 reduces hypertriglyceridemia by regulating lipid metabolism through sympathetic stimulation in adipose tissues (Specific Aim 1) and sympathetic action in the liver (Specific Aim 2). The role of sympathetic action via the neurotransmitter norepinephrine and adrenergic receptor-mediated pathways will be investigated, and their necessity in APOA4-mediated lipid metabolism will be tested. A strength of this project is the interdisciplinary collaboration between investigators with established successful collaboration and publications. The project will provide physiological, molecular, and neurochemical mechanisms underlying how APOA4 differentially regulates metabolism through sympathetic activation in various types of adipose tissues and the liver in male and female obese mice. Findings would provide impetus to develop unique, novel, targeted therapeutic applications against hypertriglyceridemia and MASLD. Importantly, this project will expose undergraduates and graduate students to meritorious research, provide students with hands-on biomedical research experience, and strengthen research environment at R15 eligible institutions.

Programming Offspring Metabolism: The Role of Milk Extracellular Vesicles in Fat Development

SUMMARY Obesity is a global health crisis, contributing significantly to the prevalence of metabolic disorders, cardiovascular diseases, and various chronic conditions. A growing body of evidence suggests that maternal obesity during pregnancy and lactation can predispose offspring to obesity and metabolic dysfunction later in life. However, the mechanisms by which maternal obesity programs these adverse outcomes in offspring remain poorly understood. Breast milk is not only a source of essential nutrients but also contains bioactive components, including extracellular vesicles (EVs), which play crucial roles in cellular communication and development. Recent studies have shown that EVs can survive digestion and enter the infant’s circulation, influencing immune and metabolic development. Despite the established link between maternal obesity and altered breast milk composition, no study has investigated the role of milk-derived EVs (mEVs) in programming offspring fat development and metabolism. Understanding this novel pathway could revolutionize our approach to preventing intergenerational transmission of obesity. Our preliminary studies using a mouse model of maternal high-fat diet-induced obesity revealed significant alterations in mEV biogenesis and cargo composition, including changes in specific miRNAs. Oral administration of mEVs from obese dams to neonatal mice increased adiposity and impaired lipid metabolism, indicating that mEVs are crucial in modulating fat development and metabolic pathways in offspring. Several key miRNAs found in mouse mEVs are conserved in human milk EVs, highlighting the potential translational relevance of our findings to human health. We hypothesize that mEVs are critical mediators of maternal obesity’s programming effects on offspring metabolism and adiposity. In specific aim 1, we will use mouse models and advanced molecular techniques (miRNA sequencing, proteomics, and lipidomics) to characterize how maternal obesity affects mEV biogenesis and the composition of their bioactive cargo. We will also evaluate how maternal dietary intake, independent of obesity, influences mEV composition. Specific aim 2 will define the programming effects of mEVs on offspring energy metabolism and obesity. In addition, we will explore whether human milk EVs from lean and obese mothers exert similar programming effects on fat development and metabolism in a mouse model. This R21 application embodies a high-risk, high-reward approach to obesity research. It ventures into uncharted territory by proposing that mEVs are novel regulators of metabolic programming, a concept that has not been explored in prior studies. The potential reward is substantial: discovering a new mechanism by which maternal obesity influences offspring health could fundamentally shift our understanding of early-life metabolic programming and lead to innovative strategies for obesity prevention. If successful, this research could open a new field of study with broad implications for maternal and child health.

Post-diagnosis changes in body composition and renal cell cancer survival

ABSTRACT Significance. Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and most lethal subtype, and there is great interest in the identification of potentially modifiable prognostic factors. Although weight status seems to be relevant, the relationship between body mass index (BMI) at diagnosis and survival among ccRCC patients indicates that mortality is lowest among those classified as overweight or obese at the time of diagnosis by BMI. This has resulted in confusion in clinical guidance for weight management among ccRCC patients. Recent work involving body composition features (adipose and muscle tissue) has provided some insight, but we do not understand how weight or body composition changes after diagnosis relate to survival, nor how these changes relate to pathological and molecular tumor features— information which is needed to resolve this controversy. Rigorous analytical approaches are further required to accurately address these questions. Innovation. Our study is highly innovative in that 1) we will be the first to leverage a large-scale cohort of ccRCC patients with multiple assessments of weight and body composition from diagnosis onward; 2) we will examine tumor characteristics, including molecular features, as potential drivers of these changes; and 3) we will use a rigorous joint modeling approach to simultaneously model the post-diagnosis trajectories of weight and body composition and their relationships with cancer outcomes in the most statistically sound manner. Our findings will inform clinical management of, and identify modifiable body composition features to improve survival for the growing number of ccRCC patients. Approach. We will use available data from the RESOLVE cohort, an NCI-funded retrospective cohort of 1,239 Stage I-III clear-cell renal cell carcinoma (ccRCC) patients diagnosed between 2000-2020 at Memorial Sloan Kettering Cancer Center. These data include clinical and patient-level factors collected from the medical record, including repeated height and weight assessments, body composition measures from existing computed tomography scans, pathological and molecular tumor characteristics, and overall survival (OS) and disease-free survival (DFS). We will use a joint modeling approach to simultaneously model changes in post-diagnosis body weight (Aim 1) and OS and DFS, as well as post-diagnosis changes in muscle and adipose tissue features (Aim 2) and OS and DFS. Models will include molecular tumor characteristics as predictors of these longitudinal trajectories. Impact. These results will provide crucial insight into the relationship between body composition changes and outcomes among ccRCC patients, and potentially identify tumor-related characteristics driving these associations. These results will resolve apparent paradoxes around the relationship between obesity and ccRCC mortality and identify potential targets for nutrition and physical activity interventions on body composition.

Endocannabinoid System Dysregulations in Binge Eating Disorder and Obesity

The Neurobiology of the Addicted Brain

Obesity and Brain – Bidirectional Influences

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

Uncovering the molecular effectors of diet and exercise

Despite the profound effects of nutrition and physical activity on human health, our understanding of the molecules mediating the salutary effects of specific foods or activities remains remarkably limited. Here, we share our ongoing studies that use unbiased and high-resolution metabolomics technologies to uncover the molecules and molecular effectors of diet and exercise. We describe how exercise stimulates the production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Ablation of Lac-Phe biosynthesis in mice increases food intake and obesity after exercise. We also describe the discovery of an orphan metabolite, BHB-Phe. Ketosis-inducible BHB-Phe is a congener of exercise-inducible Lac-Phe, produced in CNDP2+ cells when levels of BHB are high, and functions to lower body weight and adiposity in ketosis. Our data uncover an unexpected and underappreciated signaling role for metabolic fuel derivatives in mediating the cardiometabolic benefits of diet and exercise. These data also suggest that diet and exercise may mediate their physiologic effects on energy balance via a common family of molecules and overlapping signaling pathways.

The brain control of appetite: Can an old dog teach us new tricks?

It is clear that the cause of obesity is a result of eating more than you burn. It is physics. What is more complex to answer is why some people eat more than others? Differences in our genetic make-up mean some of us are slightly more hungry all the time and so eat more than others. We now know that the genetics of body-weight, on which obesity sits on one end of the spectrum, is in actuality the genetics of appetite control. In contrast to the prevailing view, body-weight is not a choice. People who are obese are not bad or lazy; rather, they are fighting their biology.

Targeting the brain to improve obesity and type 2 diabetes

The increasing prevalence of obesity and type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating energy homeostasis to accelerate the identification of new medications. Recent reports indicate that obesity medication, 5-hydroxytryptamine (5-HT, serotonin)2C receptor (5-HT2CR) agonist lorcaserin improves glycemic control in association with weight loss in obese patients with T2D. We examined whether lorcaserin has a direct effect on insulin sensitivity and how this effect is achieved. We clarify that lorcaserin dose-dependently improves glycemic control in a mouse model of T2D without altering body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin’s glucoregulatory effects, via activation of brain pro-opiomelanocortin (POMC) peptides. We observed that lorcaserin reduces hepatic glucose production and improves insulin sensitivity. These data suggest that lorcaserin’s action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Importance of perinatal hormones and diet on hypothalamic development and lifelong metabolic regulation

Some new insights into the central sensing of nutritional state and somatic stress

This talk will focus on two areas. I will firstly discuss some new data, starting with insights from rare human genetic variants, which helps to clarify the role of the central melanocortin system in the acquisition of nutrients and their disposition into growth, the acquisition of lean mass and sexual maturation . I will then discuss some aspects of the emerging biology of GDF15; a sentinel hormone conveying information regarding a range of somatic stresses to the brain.

Brain-body interactions in the metabolic/nutritional control of puberty: Neuropeptide pathways and central energy sensors

Puberty is a brain-driven phenomenon, which is under the control of sophisticated regulatory networks that integrate a large number of endogenous and environmental signals, including metabolic and nutritional cues. Puberty onset is tightly bound to the state of body energy reserves, and deregulation of energy/metabolic homeostasis is often associated with alterations in the timing of puberty. However, despite recent progress in the field, our knowledge of the specific molecular mechanisms and pathways whereby our brain decode metabolic information to modulate puberty onset remains fragmentary and incomplete. Compelling evidence, gathered over the last fifteen years, supports an essential role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine control of puberty. Kiss1 neurons are major components of the hypothalamic GnRH pulse generator, whose full activation is mandatory pubertal onset. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. However, the modulatory influence of metabolic signals (e.g., leptin) on Kiss1 neurons might be predominantly indirect and likely involves also the interaction with other transmitters and neuronal populations. In my presentation, I will review herein recent work of our group, using preclinical models, addressing the molecular mechanisms whereby Kiss1 neurons are modulated by metabolic signals, and thereby contribute to the nutritional control of puberty. In this context, the putative roles of the energy/metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1, in the metabolic control of Kiss1 neurons and puberty will be discussed. In addition, I will summarize recent findings from our team pointing out a role of central de novo ceramide signaling in mediating the impact of obesity of (earlier) puberty onset, via non-canonical, kisspeptin-related pathways. These findings are posed of translational interest, as perturbations of these molecular pathways could contribute to the alterations of pubertal timing linked to conditions of metabolic stress in humans, ranging from malnutrition to obesity, and might become druggable targets for better management of pubertal disorders.

A metabolic function of the hippocampal sharp wave-ripple

The hippocampal formation has been implicated in both cognitive functions as well as the sensing and control of endocrine states. To identify a candidate activity pattern which may link such disparate functions, we simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats. We found that clusters of sharp wave-ripples (SPW-Rs) recorded from both dorsal and ventral hippocampus reliably predicted a decrease in peripheral glucose concentrations within ~10 minutes. This correlation was less dependent on circadian, ultradian, and meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples, and was attenuated by pharmacogenetically suppressing activity of the lateral septum, the major conduit between the hippocampus and subcortical structures. Our findings demonstrate that a novel function of the SPW-R is to modulate peripheral glucose homeostasis and offer a mechanism for the link between sleep disruption and blood glucose dysregulation seen in type 2 diabetes and obesity.

Using human pluripotent stem cells to model obesity in vitro

Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets. ​

Investigating obesity-linked cortico-accumbal plasticity mechanisms underlying enhanced hedonic feeding

Long-term effects of diet-induced obesity on gut-brain communication

Rapid communication between the gut and the brain about recently consumed nutrients is critical for regulating food intake and maintaining energy homeostasis. We have shown that the infusion of nutrients directly into the gastrointestinal tract rapidly inhibits hunger-promoting AgRP neurons in the arcuate nucleus of the hypothalamus and suppresses subsequent feeding. The mechanism of this inhibition appears to be dependent upon macronutrient content, and can be recapitulated by a several hormones secreted in the gut in response to nutrient ingestion. In high-fat diet-induced obese mice, the response of AgRP neurons to nutrient-related stimuli are broadly attenuated. This attenuation is largely irreversible following weight loss and may represent a mechanism underlying difficulty with weight loss and propensity for weight regain in obesity.

Neurocircuits in control of integrative physiology

This open colloquia session is part of the special workshop entitled "Obesity at the Interface of Neuroscience and Physiology II". Abstract: Proopiomelanocortin (POMC)- and agouti related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus (ARH) are critical regulators of food intake and energy homeostasis. They rapidly integrate the energy state of the organism through sensing fuel availability via hormones, nutrient components and even rapidly upon sensory food perception. Importantly, they not only regulate feeding responses, but numerous autonomic responses including glucose and lipid metabolism, inflammation and blood pressure. More recently, we could demonstrate that sensory food cue-dependent regulation of POMC neurons primes the hepatic endoplasmic reticulum (ER) stress response to prime liver metabolism for the postpramndial state. The presentation will focus on the regulation of these neurons in control of integrative physiology, the identification of distinct neuronal circuitries targeted by these cells and finally on the broad range implications resulting from dysregulation of these circuits as a consequence of altered maternal metabolism.

Towards resolving the Protein Paradox in longevity and late-life health

Reducing protein intake (and that of key amino acids) extends lifespan, especially during mid-life and early late-life. Yet, due to a powerful protein appetite, reducing protein in the diet leads to increased food intake, promoting obesity – which shortens lifespan. That is the protein paradox. In the talk I will bring together pieces of the jigsaw, including: specific nutrient appetites, protein leverage, macronutrient interactions on appetite and ageing, the role of branched-chain amino acids and FGF-21, and then I will conclude by showing how these pieces fit together and play out in the modern industrialised food environment to result in the global pandemic of obesity and metabolic disease.

Epigenetic Reprogramming of Taste by Diet

Diets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

Contribution of c-Fos expression in the arcuate nucleus to the development of obesity in miRNA-deficient mice

Effects of a cafeteria restricted diet and oleuropein supplementation on sweet taste modifications in a cafeteria diet-induced obesity rodent model

Identification of a novel hypothalamic system controling feeding behavior and investigation of its therapeutic potential in obesity

Obesity-driven microglial activation – functional role of cerebral sterol metabolism

Obesity-induced learning deficits in the female rat are oestrous cycle-dependent and are associated with impaired tryptophan metabolism through the kynurenine pathway

Single-cell molecular and functional mapping of POMC neurons in obesity: a multi-modal approach

Butyrylcholinesterase is linked to obesity but does not regulate the appetite and glucose metabolism

FENS Forum 2024

Deconstruction of the role of CB1 receptor in CaMKII+ neurons in the context of obesity, metabolic syndrome, binge-eating, and food addiction

FENS Forum 2024

Dietary fatty acid composition drives neuroinflammation and impaired behavior in obesity

FENS Forum 2024

Differential modulation of the endocannabinoid system in binge eating disorder and obesity

FENS Forum 2024

Exposure to food-associated sensory cues during development program central response to food and obesity

FENS Forum 2024

Gut microbiota alterations and hypothalamic inflammation precede obesity in a rat model of binge eating

FENS Forum 2024

Newly synthesized fatty acid analogue (NKS-3) rescues microglial reactivity in a murine model of diet-induced obesity

FENS Forum 2024

An obesity-associated switch in vagal gut-brain communication modulates feeding behavior

FENS Forum 2024

Pleiotrophin: A bridge between obesity and neurodegenerative disorders promoting memory loss and glial alterations by modulating neuroinflammation and perineuronal nets

FENS Forum 2024