Matthias Tschöp

• University of Cincinnati

The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cell...

Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a n...

Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options...

With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for hea...

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and...

Objective The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Methods Hypothalamic, hi...

Insulin resistance is an early complication of diet-induced obesity (DIO)¹, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive β cell hypertrophy and development of type 2 diabetes². Insulin not only signals via the insulin receptor (INSR), but also promotes β cell survival, growth and function via the insulin-like...

Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to “reduce food and avoid drinking to fullness” and begin “running during the night.” Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed th...

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR–GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP...

This book sheds light on the translation of current mechanistic research on placebo effects to develop comprehensive and adequate strategies for better symptom management and treatment. This book identifies three core aspects to bridge state-of-the-art concepts with day-to-day clinical practice. First, lessons from mechanistic placebo research indi...

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amp...

Metabolic inflexibility in skeletal muscle (SkM) is closely linked to metabolic diseases. Exercise improves metabolic flexibility, rendering it a valuable discovery tool of mechanisms promoting efficient metabolism of glucose and lipids. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in SkM. We g...

GIPR:GLP-1R co-agonism improves obesity and cardio-metabolic disease with superior efficacy in both male and female mice compared to mono-agonism. We detected sex-specific differences in metabolic phenotypes, which may point to differing sensitivity for GLP-1R and/or GIPR in areas of the hypothalamus regulating energy balance (ARC, VMH, DMH) and in...

Nausea often occurs in stressful situations, such as chemotherapy or surgery. Clinically relevant placebo effects in nausea have been demonstrated, but it remains unclear whether stress has an impact on these effects. The aim of this experimental study was to investigate the interplay between acute stress and placebo effects in nausea. 80 healthy f...

The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The...

Background Agonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among the most promising drugs in clinical development for the treatment of obesity and type 2 diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia a...

Fibroblast growth factor 21 (FGF21) is generally known as a stress-induced metabolic regulator with enormous therapeutic potential to treat metabolic diseases, but a more specific role of FGF21 concerns physiological handling of alcohol in mammals. In this issue of Cell Metabolism, Choi et al. demonstrate that FGF21 mediates the recovery from alcoh...

Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosst...

Objective: Mice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic pheno...

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotro...

The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling...

Objective: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypepti...

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links...

Oxytocin-expressing paraventricular hypothalamic neurons (PVN-OT neurons) integrate afferent signals from the gut including cholecystokinin (CCK) to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVN-OT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective...

Introduction Despite growing evidence validating placebo effects in nausea, little is known about the underlying cortical mechanisms in women and men. Therefore, the present study examined sex differences and electroencephalography (EEG) characteristics of the placebo effect on nausea. Methods On 2 consecutive days, 90 healthy subjects (45 females...

Hypothalamic astrocytes are particularly affected by energy‐dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecu...

Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nu-cleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molec...

Agonism at the receptors for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular co-agonists which are among the most promising drugs in clinical development for the treatment of obesity and diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia, and thus to reduce the cardiov...

Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient e...

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are anchored at the surface of mammalian blood and tissue cells through a carboxy-terminal GPI glycolipid. Eventually, they are released into incubation medium in vitro and blood in vivo and subsequently inserted into neighboring cells, potentially leading to inappropriate surface expre...

How to adjust metabolic rate (MR) in mice that differ in body mass and composition continues to lead to controversies. Here, the challenges that reside in the analysis of mouse MR are highlighted to spur consensus on the unequivocal use of regression-based analysis to maximize reliability and relevance of conclusions.

Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects I...

Objective: Technological advances have brought a steady increase in the availability of various types of omics data, from genomics to metabolomics. Integrating these multi-omics data is a chance and challenge for systems biology; yet, tools to fully tap their potential remain scarce. Methods: We present here a fully unsupervised and versatile co...

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with pr...

Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitec...

Astrocytes are specialized glial cells that are embedded in a framework of neurons and act as an interface between neurons and the vasculature in the brain. This privileged, interconnecting position has recently been shown to render these cells crucial in the central control of systemic metabolism by allowing them to sense and convey blood-borne in...

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03347-z.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22119-x

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs), which are anchored at the surface of mammalian cultured and tissue cells through a carboxy-terminal GPI glycolipid, are susceptible to release into incubation medium and (rat and human) blood, respectively, in response to metabolic stress and ageing. Those GPI-APs with the complete GPI...

Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure1–3. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we na...

Objective We aimed to assess the spatiotemporal GLP-1 and GIP receptor signaling, trafficking and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. Methods Receptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescen...

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body’s energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons’ functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive...

Based on early experimental lesion findings, the hypothalamus was historically identified as fundamental for balancing energy intake versus expenditure. Research over the last decades has identified considerable detail of the functional specialization of the hypothalamic neurocircuitry, and how it integrates multiple energy status signals and issue...

Background Dusp8 is the first GWAS‐identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior. Methods Female, chow‐fed global Dusp8 WT and KO mice were tested in an observ...

Aims: Unimolecular peptides targeting the receptors for GLP-1 and GIP (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardio-metabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomar...

In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea,...

Recent genome-wide association studies (GWAS) identified DUSP8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes (T2D) risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specif...

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are associated with the surface of eucaryotic cells only through a covalently coupled carboxy-terminal GPI glycolipid structure which is anchored at the outer leaflet of plasma membranes. This mode of membrane association may be responsible for the recent observations that full-length G...

Aims/hypothesis: Treatment with the α3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. Methods: DMPP (10 mg/kg body weight, s.c.) was administered either in a single injecti...

Objective: Polypharmacotherapy shows superior efficacy compared to monotherapy in correcting obesity and its co-morbidities in preclinical studies and clinical trials. Female organisms have been traditionally neglected in this research potentially contributing to an increased rate of adverse advents in women. To address this disparity we herein det...

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activati...

Introduction: Tbx3 has been shown to play a role in the terminal specification of hypothalamic melanocortin neurons during neonatal development & in maintaining the plasticity of their peptidergic role in adulthood in animal experiments (1). The absence of humans with biallelic mutations in TBX3 & the conservation of the critical domains across spe...

Researchers around the globe have been mounting, accelerating and redeploying efforts across disciplines and organizations to tackle the SARS CoV-2 outbreak. However, humankind continues to be afflicted by numerous other devastating diseases in increasing numbers. Here, we outline considerations and opportunities toward striking a good balance betw...

Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature am...

Numerous studies have shown that the mere expectation improvement can alleviate symptoms in various conditions. These placebo effects often include reliable changes in central and peripheral organ systems. Here, we tested for the first time whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design,...

Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotoci...

Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesi...

The steadily increasing amount of newly generated omics data of various types from genomics to metabolomics is a chance and a challenge to systems biology. To fully use its potential, one key is the meaningful integration of different types of omics. We here present a fully unsupervised and versatile correlation-based method, termed Correlation gui...

Glycosylphosphatidylinositol-anchored proteins (GPI-AP) with the complete glycolipid anchor attached are present in rat and human serum at amounts which are lower in insulin-resistant/obese rats compared to normal ones. These findings prompted further evaluation of the potential of full-length GPI-AP for the prediction and stratification of metabol...

Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type‐2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucago...

Dual-specificity phosphatase 8 (Dusp8) acts as physiological inhibitor for the MAPKs Jnk, Erk and p38 which are involved in regulating multiple CNS processes. While Dusp8 expression levels are high in limbic areas such as the hippocampus, the functional role of Dusp8 in hippocampus morphology, MAPK-signaling, neurogenesis and apoptosis as well as i...

Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucago...

Excessive circulating fatty acids (FAs) have been proposed to promote insulin resistance of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate insulin resistance. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby...

The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical st...

Obesity is taking worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar AMP-DNM which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in...

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell prol...

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatri...

Objective: Obesity and type-2 diabetes (T2D) are metabolic diseases that represent a critical health problem worldwide. Metabolic disease is differentially associated with fat distribution, while visceral white adipose tissue (VAT) is particularly prone to obesity-associated inflammation. Next to their canonical function of immune suppression, reg...

Background The worldwide rise in overweight and obesity is paralleled by an increasing prevalence of type-2 diabetes. Apart from bariatric surgery, treatment options to decrease body weight are often underwhelming. Innovative pharmacological options are required to cope with the global “diabesity” pandemic. Objectives Particular novel pharmacologi...

Background/objectives: Individuals carrying loss-of-function gene mutations for the adipocyte hormone leptin are morbidly obese, but respond favorably to replacement therapy. Recombinant leptin is however largely ineffective for the vast majority of obese individuals due to leptin resistance. One theory underlying leptin resistance is impaired lep...

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed Regnase-3 –deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell–specific deletions of Regnase...

To study the possibility that certain components of eukaryotic plasma membranes are released under certain (patho)physiological conditions, a chip-based sensor was developed for the detection of cell surface proteins, which are anchored at the outer leaflet of eukaryotic plasma membranes by a covalently attached glycolipid, exclusively, and might b...

Background: Pharmacotherapies targeting motivational aspects of feeding and palatable food reward, while sparing mood and cognitive function, represent an alluring approach to reverse obesity and maintain weight loss in an obesogenic environment. A novel glucagon-like peptide-1/dexamethasone (GLP-1/Dexa) conjugate, developed to selectively activat...

Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegy...