Dudley Lamming | University of Wisconsin-Madison (original) (raw)

Papers by Dudley Lamming

Cell Research

The mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates diverse metabolic processes in r... more The mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates diverse metabolic processes in response to nutrient stimuli and environmental cues. In a recent issue of Science, Shin et al. report the identification of a lysosomal G proteincoupled receptor-like protein that binds to cholesterol and couples the availability of this critical macronutrient to mTORC1 activation. The mechanistic Target of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that is inhibited by rapamycin, a small molecule discovered in samples collected on Easter Island almost 50 years ago. Over the past two decades, it has become clear that mTOR, in particular, mTOR complex 1 (mTORC1), plays a central role in essential cellular processes and metabolism, functioning as a signaling node to integrate cellular nutrient and hormonal cues to appropriately coordinate anabolic and catabolic processes with the availability of nutrients. 1 Some of the best characterized substrates of mTORC1 include S6K1, 4E-BP1, and ULK1, through which mTORC1 regulates processes including protein translation, ribosome biogenesis, lipogenesis, nucleotide synthesis, and autophagy. mTORC1 kinase activity is regulated through control of its interaction with the small GTPase Rheb at the lysosomal surface. The recruitment of mTORC1 to the lysosomal surface by the availability of specific nutrients, particularly amino acids, is described in detail elsewhere. 2 Briefly, mTORC1 is recruited to the lysosomal surface by heterodimeric complexes of the Rag family of small GTPases; when these Rag proteins are loaded with GTP or GDP in a specific configuration, they localize mTORC1 to the lysosomal surface. The nucleotide loading state of the Rag GTPases is controlled by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Of particular relevance, the GATOR1 complex functions as a GAP for RagA and RagB, while a second complex, GATOR2, acts to inhibit GATOR1 GAP activity via unknown mechanisms. 3 As shown in Fig. 1, specific nutrient sensors for amino acids including leucine and arginine and the methionine metabolite SAM act by binding to and inhibiting the activity of either GATOR2 (e.g., Sestrin1/2/3 and CASTOR1/2) or GATOR1 (SAM-TOR). An unknown sensor of the glycolysis intermediate DHAP also signals to mTORC1 via GATOR1. The sensing of other amino acids involves a low-affinity lysosomal amino acid transporter, SLC38A9, which may signal to mTORC1 via the Ragulator, which has GEF activity toward RagA/RagB. If mTORC1 activity indicates the availability of nutrients required to fuel anabolic processes and serve as building blocks for macromolecule synthesis, we might expect that mTORC1

Nature Aging, 2021

Protein-restricted diets promote health and longevity in many species. While the precise componen... more Protein-restricted diets promote health and longevity in many species. While the precise components of a protein-restricted diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of protein restriction can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in life span and a reduction in frailty in male, but not female, wild-type mice when they undergo lifelong feeding. Our results demonstrate that restricting dietary BCAAs can increase health span and longevity in mice and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

This study describes a mouse model of progressive resistance exercise that utilizes a full-body/m... more This study describes a mouse model of progressive resistance exercise that utilizes a full-body/multi-joint exercise (weight pulling) along with a training protocol that mimics a traditional human paradigm (3 training sessions per week, ∼8-12 repetitions per set, 2 minutes of rest between sets, ∼2 maximal-intensity sets per session, last set taken to failure, and a progressive increase in loading that is based on the individual’s performance). We demonstrate that weight pulling can induce an increase in the mass of numerous muscles throughout the body. The relative increase in muscle mass is similar to what has been observed in human studies, and it is associated with the same type of long-term adaptations that occur in humans (e.g., fiber hypertrophy, myonuclear accretion, and in some instances a fast-to-slow transition in Type II fiber composition). Moreover, we demonstrate that weight pulling can induce the same type of acute responses that are thought to drive these long-term ad...

Metabolites, 2021

The transition from β-cell compensation to β-cell failure is not well understood. Previous works ... more The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found num...

eLife, 2020

Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan a... more Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, an...

Nature Protocols, 2020

A series of techniques (echocardiography, novel object recognition, grip strength, rotarod, gluco... more A series of techniques (echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure) are used to assess the health of mice. TWEET Assessing the health of aging mice COVER TEASER Aging mice health assessment RELATED LINKS Key reference(s) using this protocol Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nature communications 4, 2192,

Cell Reports, 2019

Highlights d Calorie restriction (CR) extends lifespan and improves insulin sensitivity d Mice la... more Highlights d Calorie restriction (CR) extends lifespan and improves insulin sensitivity d Mice lacking adipose mTORC2 are insulin resistant, even on a CR diet d CR promotes fitness and longevity in mice lacking adipose mTORC2 d Improved organismal insulin sensitivity does not mediate the beneficial effects of CR

Aging Cell, 2019

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Nature Communications, 2019

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan a... more Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1...

The Journals of Gerontology: Series A, 2019

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamyci... more Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects ...

Scientific Reports, 2019

Obesity and type 2 diabetes are increasing in prevalence around the world, and there is a clear n... more Obesity and type 2 diabetes are increasing in prevalence around the world, and there is a clear need for new and effective strategies to promote metabolic health. A low protein (LP) diet improves metabolic health in both rodents and humans, but the mechanisms that underlie this effect remain unknown. The gut microbiome has recently emerged as a potent regulator of host metabolism and the response to diet. Here, we demonstrate that a LP diet significantly alters the taxonomic composition of the gut microbiome at the phylum level, altering the relative abundance of Actinobacteria, Bacteroidetes, and Firmicutes. Transcriptional profiling suggested that any impact of the microbiome on liver metabolism was likely independent of the microbiome-farnesoid X receptor (FXR) axis. We therefore tested the ability of a LP diet to improve metabolic health following antibiotic ablation of the gut microbiota. We found that a LP diet promotes leanness, increases energy expenditure, and improves glyc...

Scientific Reports, 2018

Type 2 diabetes is an age-and-obesity associated disease driven by impairments in glucose homeost... more Type 2 diabetes is an age-and-obesity associated disease driven by impairments in glucose homeostasis that ultimately result in defective insulin secretion from pancreatic β-cells. To deconvolve the effects of age and obesity in an experimental model of prediabetes, we fed young and aged mice either chow or a short-term high-fat/high-sucrose Western diet (WD) and examined how weight, glucose tolerance, and β-cell function were affected. Although WD induced a similar degree of weight gain in young and aged mice, a high degree of heterogeneity was found exclusively in aged mice. Weight gain in WD-fed aged mice was well-correlated with glucose intolerance, fasting insulin, and in vivo glucose-stimulated insulin secretion, relationships that were not observed in young animals. Although β-cell mass expansion in the WD-fed aged mice was only three-quarters of that observed in young mice, the islets from aged mice were resistant to the sharp WD-induced decline in ex vivo insulin secretion ...

Aging cell, Jan 27, 2018

The membrane transporter AT-1/SLC33A1 translocates cytosolic acetyl-CoA into the lumen of the end... more The membrane transporter AT-1/SLC33A1 translocates cytosolic acetyl-CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT-1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT-1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT-1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of syste...

Cell, Jan 2, 2017

Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and com... more Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP, engaging the innate sensor stimulator of interferon genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic target of rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER...

Nutrition and Healthy Aging, 2017

Recently, it has become apparent that dietary macronutrient composition has a profound impact on ... more Recently, it has become apparent that dietary macronutrient composition has a profound impact on metabolism, health and even lifespan. Work from many laboratories now suggest that dietary protein quality-the precise amino acid composition of the diet, as well as possibly the source of dietary protein-may also be critical in regulating the impact of diet on health. Perhaps in part due to the naturally low methionine content of plants, vegan diets are associated with a decreased risk of diabetes and improved insulin sensitivity, but this association is confounded by the lower overall protein intake of vegans. Here, we test the effect of consuming isocaloric rodent diets with similar amino acid profiles derived from either plant protein or dairy protein. We find that male C57BL/6J mice consuming either diet have similar glycemic control, as assessed by glucose, insulin, and pyruvate tolerance tests, and have similar overall body composition. We conclude that short-term feeding of plant protein has no positive or negative effect on the metabolic health of young male C57BL/6J mice, and suggest that dietary interventions that alter either dietary protein levels or the levels of specific essential amino acids are more likely to improve metabolic health than alterations in dietary protein source.

The Journal of clinical investigation, Jan 5, 2017

The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of ... more The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor α ...

Molecular and Cellular Endocrinology, 2017

All organisms need to be capable of adapting to changes in the availability and composition of nu... more All organisms need to be capable of adapting to changes in the availability and composition of nutrients. Over 75 years ago, researchers discovered that a calorie restricted (CR) diet could significantly extend the lifespan of rats, and since then a CR diet has been shown to increase lifespan and healthspan in model organisms ranging from yeast to non-human primates. In this review, we discuss the effects of a CR diet on metabolism and healthspan, and highlight emerging evidence that suggests that dietary composition-the precise macronutrients that compose the diet-may be just as important as caloric content. In particular, we discuss recent evidence that suggests protein quality may influence metabolic health. Finally, we discuss key metabolic pathways which may influence the response to CR diets and altered macronutrient composition. Understanding the molecular mechanisms responsible for the effects of CR and dietary composition on health and longevity may allow the design of novel therapeutic approaches to agerelated diseases. Calorie restriction promotes health and longevity Calorie restriction (CR), a dietary intervention in which calories are reduced while maintaining adequate levels of micronutrients, was first discovered to extend the lifespan of rats more than 75 years ago (McCay et al., 1935). Since that time, a CR diet has been shown to extend lifespan in many model organisms including yeast, worms, flies, rodents, and nonhuman primates (

Cell Reports, 2016

Highlights d Protein-restricted (PR) and branched-chain amino acid (BCAA)-restricted diets improv... more Highlights d Protein-restricted (PR) and branched-chain amino acid (BCAA)-restricted diets improve metabolic health d Decreasing dietary BCAAs recapitulates many of the benefits of a PR diet d Low BCAA diet improves metabolic health independently from changes in energy balance d Dietary protein quality regulates metabolic health independently from protein quantity

Diabetes, Sep 9, 2016

Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, cu... more Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic β cells. To investigate the effects of age on β cell metabolism, we established a novel assay to directly image islet metabolism using NAD(P)H fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NAD(P)H FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (≥ 24 months), resulting from 52% and 57% defects in flux through complex I and II of the electron transport chain. However, insulin secretion and glucose tolerance are preserved in aged mouse islets by the heightened metabolic sensitivity of the β cell triggering pathway, an adaptation clearly encoded in the metabolic and Ca(2+) oscillations that trigger insulin release (Ca(2+) plateau fraction: young, 0.380 ± 0.007; aged, 0...