Digesting the complex metabolic effects of diet on the host and microbiome.

The past 50 years of interdisciplinary research in humans and model organisms has delivered unprecedented insights into the mechanisms through which diet affects energy balance. However, translating these results to prevent and treat obesity and its associated diseases remains challenging. Given the vast scope of this literature, we focus this Review on recent conceptual advances in molecular nutrition targeting the management of energy balance, including emerging dietary and pharmaceutical interventions and their interactions with the human gut microbiome. Notably, multiple current dietary patterns of interest embrace moderate-to-high fat intake or prioritize the timing of eating over macronutrient intake. Furthermore, the rapid expansion of microbiome research findings has complicated multiple longstanding tenets of nutrition while also providing new opportunities for intervention. Continued progress promises more precise and reliable dietary recommendations that leverage our growing knowledge of the microbiome, the changing landscape of clinical interventions, and our molecular understanding of human biology.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Transforming obesity: The advancement of multi-receptor drugs.

For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.

Embracing cancer complexity: Hallmarks of systemic disease.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

Translational potential of mouse models of human metabolic disease.

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

Diabetes mellitus-Progress and opportunities in the evolving epidemic.

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

Breaking down a gut-to-brain circuit that prevents malabsorption.

The ileal brake is an important reflex that ensures proper absorption of nutrients. This involves intestinal GLP-1 release, which recruits an enteric-sympathetic-spinal pathway to inhibit gastric motility and appetite. This visceral alarm system could be targeted to treat obesity and gastrointestinal dysfunction.

Local hyperthermia therapy induces browning of white fat and treats obesity.

Beige fat plays key roles in the regulation of systemic energy homeostasis; however, detailed mechanisms and safe strategy for its activation remain elusive. In this study, we discovered that local hyperthermia therapy (LHT) targeting beige fat promoted its activation in humans and mice. LHT achieved using a hydrogel-based photothermal therapy activated beige fat, preventing and treating obesity in mice without adverse effects. HSF1 is required for the effects since HSF1 deficiency blunted the metabolic benefits of LHT. HSF1 regulates Hnrnpa2b1 (A2b1) transcription, leading to increased mRNA stability of key metabolic genes. Importantly, analysis of human association studies followed by functional analysis revealed that the HSF1 gain-of-function variant p.P365T is associated with improved metabolic performance in humans and increased A2b1 transcription in mice and cells. Overall, we demonstrate that LHT offers a promising strategy against obesity by inducing beige fat activation via HSF1-A2B1 transcriptional axis.

Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome.

How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.

Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.

The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.

White adipocyte dysfunction and obesity-associated pathologies in humans.

The prevalence of obesity and associated chronic diseases continues to increase worldwide, negatively impacting on societies and economies. Whereas the association between excess body weight and increased risk for developing a multitude of diseases is well established, the initiating mechanisms by which weight gain impairs our metabolic health remain surprisingly contested. In order to better address the myriad of disease states associated with obesity, it is essential to understand adipose tissue dysfunction and develop strategies for reinforcing adipocyte health. In this Review we outline the diverse physiological functions and pathological roles of human white adipocytes, examining our current knowledge of why white adipocytes are vital for systemic metabolic control, yet poorly adapted to our current obesogenic environment.

Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care.

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.

Macrophage function in adipose tissue homeostasis and metabolic inflammation.

Obesity-related metabolic organ inflammation contributes to cardiometabolic disorders. In obese individuals, changes in lipid fluxes and storage elicit immune responses in the adipose tissue (AT), including expansion of immune cell populations and qualitative changes in the function of these cells. Although traditional models of metabolic inflammation posit that these immune responses disturb metabolic organ function, studies now suggest that immune cells, especially AT macrophages (ATMs), also have important adaptive functions in lipid homeostasis in states in which the metabolic function of adipocytes is taxed. Adverse consequences of AT metabolic inflammation might result from failure to maintain local lipid homeostasis and long-term effects on immune cells beyond the AT. Here we review the complex function of ATMs in AT homeostasis and metabolic inflammation. Additionally, we hypothesize that trained immunity, which involves long-term functional adaptations of myeloid cells and their bone marrow progenitors, can provide a model by which metabolic perturbations trigger chronic systemic inflammation.

Fighting for Fat: Gluttonous Tumors and Starved T Cells.

In this issue of Cell, Ringel et al. reveal a link between lipid utilization in the tumor microenvironment and anti-tumor immunity in obese mice. These findings provide one explanation for how obesity worsens cancer outcomes and may point to a new metabolic approach to treating some cancers.

Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

SnapShot: FABP Functions.

Fatty acid binding proteins (FABPs) serve as intracellular chaperones for fatty acids and other hydrophobic ligands inside cells. Recent studies have demonstrated new functions of individual members of the FABP family. This Snapshot describes the overall functions of FABPs in health and disease and highlights emerging roles of adipose FABP (A-FABP) and epidermal FABP (E-FABP) in the fields of obesity, chronic inflammation, and cancer development. To view this SnapShot, open or download the PDF.

Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.

Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.

A MicroRNA Linking Human Positive Selection and Metabolic Disorders.

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.