Mutant and curli-producing E. coli enhance the disease phenotype in a hSOD1-G93A mouse model of ALS.

The gut microbiome is a potential non-genetic contributing factor for Amyotrophic Lateral Sclerosis. Differences in gut microbial communities have been detected between ALS subjects and healthy controls, including an increase in Escherichia coli in ALS subjects. E. coli and other gram-negative bacteria produce curli proteins, which are functional bacterial amyloids. We examined whether long-term curli overexposure in the gut can exacerbate the development and progression of ALS. We utilized the slow-developing hSOD1-G93A mouse model of ALS with their C57BL/6J WT littermate controls, including males and females, with a total of 91 animals. These mice were on a normal chow diet and fed curli-producing or curli-nonproducing (mutant) E. coli in applesauce (vehicle) 3 times/week, from 1 through 7 months of age. Male hSOD1 mice demonstrated gradual slowing in running speed month 4 onwards, while females exhibited no signs of locomotive impairment even at 7 months of age. Around the same time, male hSOD1 mice showed a gradual increase in frequency of peripheral CD19+ B cells. Among the male hSOD1 group, chronic gut exposure to curli-producing E. coli led to significant shifts in α- and ß-diversities. Curli-exposed males showed suppression of immune responses in circulation, but an increase in markers of inflammation, autophagy and protein turnover in skeletal muscle. Some of these markers were also changed in mutant E. coli-exposed mice, including astrogliosis in the brainstem and demyelination in the lumbar spinal cord. Overall, chronic overexposure to a commensal bacteria like E. coli led to distant organ pathology in our model, without the presence of a leaky gut at 6 months. Mechanisms underlying gut-distant organ communication are of tremendous interest to all disciplines.

Ecological predictors of mosquito population and arbovirus transmission synchrony estimates.

Quantifying synchrony in species population fluctuations and determining its driving factors can inform multiple aspects of ecological and epidemiological research and policy decisions. We examined seasonal mosquito and arbovirus surveillance data collected in Connecticut, United States from 2001 to 2020 to quantify spatial relationships in 19 mosquito species and 7 arboviruses timeseries accounting for environmental factors such as climate and land cover characteristics. We determined that mosquito collections, on average, were significantly correlated up to 10 km though highly variable among the examined species. Few arboviruses displayed any synchrony and significant maximum correlated distances never exceeded 5 km. After accounting for distance, mixed effects models showed that mosquito or arbovirus identity explained more variance in synchrony estimates than climate or land cover factors. Correlated mosquito collections up to 10-20 km suggest that mosquito control operations for nuisance and disease vectors alike must expand treatment zones to regional scales for operations to have population-level impacts. Species identity matters as well, and some mosquito species will require much larger treatment zones than others. The much shorter correlated detection distances for arboviruses reinforce the notion that focal-level processes drive vector-borne pathogen transmission dynamics and risk of spillover into human populations.

Multi-Year Comparison of Community- and Species-Level West Nile Virus Antibody Prevalence in Birds from Atlanta, Georgia and Chicago, Illinois, 2005-2016.

West Nile virus (WNV) is prevalent in the United States but shows considerable variation in transmission intensity. The purpose of this study was to compare patterns of WNV seroprevalence in avian communities sampled in Atlanta, Georgia and Chicago, Illinois during a 12-year period (Atlanta 2010-2016; Chicago 2005-2012) to reveal regional patterns of zoonotic activity of WNV. WNV antibodies were measured in wild bird sera using ELISA and serum neutralization methods, and seroprevalence among species, year, and location of sampling within each city were compared using binomial-distributed generalized linear mixed-effects models. Seroprevalence was highest in year-round and summer-resident species compared with migrants regardless of region; species explained more variance in seroprevalence within each city. Northern cardinals were the species most likely to test positive for WNV in each city, whereas all other species, on average, tested positive for WNV in proportion to their sample size. Despite similar patterns of seroprevalence among species, overall seroprevalence was higher in Atlanta (13.7%) than in Chicago (5%). Location and year of sampling had minor effects, with location explaining more variation in Atlanta and year explaining more variation in Chicago. Our findings highlight the nature and magnitude of regional differences in WNV urban ecology.

Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.

Bridging integrator 1 (BIN1) is the second most prevalent genetic risk factor identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease. BIN1 encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. In vitro evidence suggests that BIN1 can directly bind to tau in the cytosol. In addition, BIN1's function limits extracellular tau seed uptake by endocytosis and subsequent propagation as well as influences tau release through exosomes. However, the in vivo roles of BIN1 in tau pathogenesis and tauopathy-mediated neurodegeneration remain uncharacterized. We generated conditional knockout mice with a selective loss of Bin1 expression in the forebrain excitatory neurons and oligodendrocytes in P301S human tau transgenic background (line PS19). PS19 mice develop age-dependent tau neuropathology and motor deficits and are commonly used to study Alzheimer's disease tau pathophysiology. The severity of motor deficits and neuropathology was compared between experimental and control mice that differ with respect to forebrain BIN1 expression. BIN1's involvement in tau pathology and neuroinflammation was quantified by biochemical methods and immunostaining. Transcriptome changes were profiled by RNA-sequencing analysis to gain molecular insights. The loss of forebrain BIN1 expression in PS19 mice exacerbated tau pathology in the somatosensory cortex, thalamus, spinal cord and sciatic nerve, accelerated disease progression and caused early death. Intriguingly, the loss of BIN1 also mitigated tau neuropathology in select regions, including the hippocampus, entorhinal/piriform cortex, and amygdala, thus attenuating hippocampal synapse loss, neuronal death, neuroinflammation and brain atrophy. At the molecular level, the loss of forebrain BIN1 elicited complex neuronal and non-neuronal transcriptomic changes, including altered neuroinflammatory gene expression, concomitant with an impaired microglial transition towards the disease-associated microglial phenotype. These results provide crucial new information on in vivo BIN1 function in the context of tau pathogenesis. We conclude that forebrain neuronal BIN1 expression promotes hippocampal tau pathogenesis and neuroinflammation. Our findings highlight an exciting region specificity in neuronal BIN1 regulation of tau pathogenesis and reveal cell-autonomous and non-cell-autonomous mechanisms involved in BIN1 modulation of tau neuropathology.

Impacts of Lysinibacillus sphaericus on mosquito larval community composition and larval competition between Culex pipiens and Aedes albopictus.

Effectiveness of mosquito larvicide active ingredients (AI), such as Lysinibacillus sphaericus, varies between species, yet little is known regarding how differential effectiveness manifests in larval communities in applied settings. To examine how differential effectiveness of L. sphaericus influences larval community dynamics, we performed two experiments. We performed a field experiment in which containers were seeded with a standardized nutrient treatment, mosquitoes colonized the containers, and then containers received one of three L. sphaericus applications. We then performed competition assays between Culex pipiens and Aedes albopictus in low nutrient environments using multiple interspecific ratios and the presence/absence of a low dose of L. sphaericus. Field results demonstrated elimination of Culex spp. from treated containers while container breeding Aedes spp. proliferated across all treatments. Lysinibacillus sphaericus did not influence competition between Cx. pipiens and Ae. albopictus, and the L. sphaericus application eliminated Cx. pipiens in all treatment replicates while survival of Ae. albopictus was similar between treated and untreated containers across interspecific ratios. Lysinibacillus sphaericus is an effective AI for control of Culex spp. However, different AIs should be utilized in habitats containing non-Culex genera while a mix of AIs should be utilized where coexistence of multiple genera is expected or confirmed.

The community-wide effectiveness of municipal larval control programs for West Nile virus risk reduction in Connecticut, USA.

BACKGROUND: Mosquito larval control through the use of insecticides is the most common strategy for suppressing West Nile virus (WNV) vector populations in Connecticut (CT), USA. To evaluate the ability of larval control to reduce entomological risk metrics associated with WNV, we performed WNV surveillance and assessments of municipal larvicide application programs in Milford and Stratford, CT in 2019 and 2020. Each town treated catch basins and nonbasin habitats (Milford only) with biopesticide products during both WNV transmission seasons. Adult mosquitoes were collected weekly with gravid and CO2 -baited light traps and tested for WNV; larvae and pupae were sampled weekly from basins within 500 m of trapping sites, and Culex pipiens larval mortality was determined with laboratory bioassays of catch basin water samples. RESULTS: Declines in 4th instar larvae and pupae were observed in catch basins up to 2-week post-treatment, and we detected a positive relationship between adult female C. pipiens collections in gravid traps and pupal abundance in basins. We also detected a significant difference in total light trap collections between the two towns. Despite these findings, C. pipiens adult collections and WNV mosquito infection prevalence in gravid traps were similar between towns. CONCLUSION: Larvicide applications reduced pupal abundance and the prevalence of host-seeking adults with no detectable impact on entomological risk metrics for WNV. Further research is needed to better determine the level of mosquito larval control required to reduce WNV transmission risk.

Progression of Nonmotor Symptoms in Parkinson's Disease by Sex and Motor Laterality.

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n = 489), compared to healthy controls, HC (n = 241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n = 81). The Parkinson's Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females reported significantly increased thermoregulatory dysfunction and anxious mood over 7 years and significantly more constipation during the first 4 years after PD onset. Laterality Differences. At onset, PD subjects with right-sided motor predominance reported significantly higher autonomic dysfunction. Subjects with left-sided motor predominance experienced significantly more anxious mood at onset which continued as Parkinson's progressed. In conclusion, males experienced increased NMS burden in Parkinson's disease. Laterality of motor symptoms did not significantly influence NMS progression, except anxious mood. We analyzed NMS in a large cohort of PD patients, and these data are valuable to improve PD patients' quality of life by therapeutically alleviating nonmotor symptoms.

NEVBD Pesticide Resistance Monitoring Network: Establishing a Centralized Network to Increase Regional Capacity for Pesticide Resistance Detection and Monitoring.

Pesticide resistance in arthropod vectors of disease agents is a growing issue globally. Despite the importance of resistance monitoring to inform mosquito control programs, no regional monitoring programs exist in the United States. The Northeastern Regional Center for Excellence in Vector-Borne Diseases (NEVBD) is a consortium of researchers and public health practitioners with a primary goal of supporting regional vector control activities. NEVBD initiated a pesticide resistance monitoring program to detect resistant mosquito populations throughout the northeastern United States. A regionwide survey was distributed to vector control agencies to determine needs and refine program development and in response, a specimen submission system was established, allowing agencies to submit Culex pipiens (L.) (Diptera:Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) for pesticide resistance testing. NEVBD also established larvicide resistance diagnostics for Bacillus thuringiensis israelensis (Bti) and methoprene. Additional diagnostics were developed for Cx. pipiens resistance to Lysinibacillus sphaericus. We received 58 survey responses, representing at least one agency from each of the 13 northeastern U.S. states. Results indicated that larvicides were deployed more frequently than adulticides, but rarely paired with resistance monitoring. Over 18,000 mosquitoes were tested from six states. Widespread low-level (1 × LC-99) methoprene resistance was detected in Cx. pipiens, but not in Ae. albopictus. No resistance to Bti or L. sphaericus was detected. Resistance to pyrethroids was detected in many locations for both species. Our results highlight the need for increased pesticide resistance testing in the United States and we provide guidance for building a centralized pesticide resistance testing program.

Increased mosquito abundance and species richness in Connecticut, United States 2001-2019.

Historical declines in multiple insect taxa have been documented across the globe in relation to landscape-level changes in land use and climate. However, declines have either not been universally observed in all regions or examined for all species. Because mosquitoes are insects of public health importance, we analyzed a longitudinal mosquito surveillance data set from Connecticut (CT), United States (U.S.) from 2001 to 2019 to identify changes in mosquito community composition over time. We first analyzed annual site-level collections and metrics of mosquito community composition with generalized linear/additive mixed effects models; we also examined annual species-level collections using the same tools. We then examined correlations between statewide collections and weather variables as well as site-level collections and land cover classifications. We found evidence that the average trap night collection of mosquitoes has increased by ~ 60% and statewide species richness has increased by ~ 10% since 2001. Total species richness was highest in the southern portion of CT, likely due to the northward range expansion of multiple species within the Aedes, Anopheles, Culex, and Psorophora genera. How the expansion of mosquito populations in the northeast U.S. will alter mosquito-borne pathogen transmission in the region will require further investigation.

What Are the Molecular Mechanisms by Which Functional Bacterial Amyloids Influence Amyloid Beta Deposition and Neuroinflammation in Neurodegenerative Disorders?

Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.

Patterns of mosquito and arbovirus community composition and ecological indexes of arboviral risk in the northeast United States.

BACKGROUND: In the northeast United States (U.S.), mosquitoes transmit a number of arboviruses, including eastern equine encephalitis, Jamestown Canyon, and West Nile that pose an annual threat to human and animal health. Local transmission of each arbovirus may be driven by the involvement of multiple mosquito species; however, the specificity of these vector-virus associations has not been fully quantified. METHODOLOGY: We used long-term surveillance data consistently collected over 18 years to evaluate mosquito and arbovirus community composition in the State of Connecticut (CT) based on land cover classifications and mosquito species-specific natural histories using community ecology approaches available in the R package VEGAN. We then used binomial-error generalized linear mixed effects models to quantify species-specific trends in arbovirus detections. PRIMARY RESULTS: The composition of mosquito communities throughout CT varied more among sites than among years, with variation in mosquito community composition among sites explained mostly by a forested-to-developed-land-cover gradient. Arboviral communities varied equally among sites and years, and only developed and forested wetland land cover classifications were associated with the composition of arbovirus detections among sites. Overall, the avian host arboviruses, mainly West Nile and eastern equine encephalitis, displayed the most specific associations among mosquito species and sites, while in contrast, the mammalian host arboviruses (including Cache Valley, Jamestown Canyon, and Potosi) associated with a more diverse mix of mosquito species and were widely distributed throughout CT. CONCLUSIONS: We find that avian arboviruses act as vector specialists infecting a few key mosquito species that associate with discrete habitats, while mammalian arboviruses are largely vector generalists infecting a wide diversity of mosquito species and habitats in the region. These distinctions have important implications for the design and implementation of mosquito and arbovirus surveillance programs as well as mosquito control efforts.

Feeding Success and Host Selection by Culex quinquefasciatus Say Mosquitoes in Experimental Trials.

Arthropod vector feeding preferences are defined as an overutilization of a particular host species given its abundance in relationship to other species in the community. Numerous methods exist to quantify vector feeding preferences; however, controlled host choice experiments are generally an underutilized approach. In this report, we present results from controlled vector host choice experiments using Culex quinquefasciatus Say (Diptera: Culicidae) mosquitoes and wild avian hosts identified as important contributors to West Nile virus (WNv) transmission in Atlanta, Georgia, United States. In each experiment, we allowed lab-reared F1Cx. quinquefasciatus to feed freely overnight on two avian individuals of a different species (i.e., northern cardinals, American robins, blue jays, brown thrashers, and gray catbirds). We then estimated WNv transmission potential using vectorial capacity and R0. We found that mosquito blood feeding success was extremely variable among experimental replicates and that patterns of host choice only occasionally aggregated to a particular bird species. Vectorial capacity was highest for American robins and blue jays due to these species' higher reservoir competence for WNv and greater probabilities of mosquito selection of these species. Despite species-specific differences in vectorial capacity, total community capacity was similar among species pairs. R0 estimates were qualitatively similar to capacity, and R0 was below and above unity across species pairs. Our results provide empirical evidence that C. quinquefasciatus is an opportunistic blood feeder and highlight how variability in vector-host contact rates as well as host community composition can influence the likelihood of WNv transmission in avian communities.

Larviciding Culex spp. (Diptera: Culicidae) Populations in Catch Basins and Its Impact on West Nile Virus Transmission in Urban Parks in Atlanta, GA.

In urban environments, road-side catch basins are common larval habitats of Culex spp. (Diptera: Culicidae) mosquitoes and important targets of larval control in areas subject to West Nile virus (WNv) transmission. We quantified the impact of larviciding basins on Culex spp. populations and WNv infection prevalence by treating basins in and around urban parks in Atlanta, GA, using Mosquito Dunks and Bits (active ingredient, a.i., Bacillus thuringiensis subsp. isrealensis, Dunks-10.31%, Bits-2.86%) and Altosid 30-Day Briquets (a.i., S-methoprene 8.62%) in two separate seasons. Treatments were coupled with WNv surveillance using gravid traps and aspiration of adults resting in basins. Larviciding led to >90% reductions in Culex spp. larval and pupal collections (Dunks/Bits) and >90% pupal mortality (Briquets) in treated sites during treatment periods; however, we did not observe significant reductions in Culex spp. collections in gravid traps (general linear mixed-effects model [GLMM] result, P > 0.1) or in adults collected resting in basins (GLMM, P > 0.5). In addition, WNv infection prevalence in Culex spp. mosquitoes was similar between treated and untreated sites (GLMM, P > 0.05). Larval control remains important for controlling WNv in Atlanta; however, at the scale and frequency applied in our study, larval control alone may not lead to meaningful reductions in adult populations and WNv infection prevalence. A greater understanding of the annual dynamics of Culex spp. breeding and the importance of basins as Culex spp. larval habitats are needed to meaningfully affect WNv in cities such as Atlanta.

Diazepam Toxicity Presenting as a Dementia Disorder.

The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer's disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer's disease or another dementing disorder if not for the systematic investigation to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient's cognition improved greatly.

TAK1 regulates skeletal muscle mass and mitochondrial function.

Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-ß-activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism.

Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease.

Skeletal muscle is the most abundant tissue in the human body and can adapt its mass as a consequence of physical activity, metabolism, growth factors, and disease conditions. Skeletal muscle contains an extensive network of endoplasmic reticulum (ER), called sarcoplasmic reticulum, which plays an important role in the regulation of proteostasis and calcium homeostasis. In many cell types, environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen that ultimately leads to ER stress. To alleviate the stress and restore homeostasis, the ER activates a signaling network called the unfolded protein response (UPR). The UPR has three arms, which regulate protein synthesis and expression of many ER chaperone and regulatory proteins. However, the role of individual UPR pathways in skeletal muscle has just begun to be investigated. Recent studies suggest that UPR pathways play pivotal roles in muscle stem cell homeostasis, myogenic differentiation, and regeneration of injured skeletal muscle. Moreover, markers of ER stress and the UPR are activated in skeletal muscle in diverse conditions such as exercise, denervation, starvation, high fat diet, cancer cachexia, and aging. Accumulating evidence also suggests that ER stress may have important roles in the pathogenesis of inflammatory myopathies and genetic muscle disorders. The purpose of this review article is to discuss the role and potential mechanisms by which ER stress and the individual arms of the UPR regulate skeletal muscle formation, plasticity, and function in various physiological and pathophysiological conditions.

Transmission Electron Microscopy for Analysis of Mitochondria in Mouse Skeletal Muscle.

Skeletal muscle is the most abundant tissue in the human body and regulates a variety of functions including locomotion and whole-body metabolism. Skeletal muscle has a plethora of mitochondria, the organelles that are essential for aerobic generation of ATP which provides the chemical energy to fuel vital functions such as contraction. The number of mitochondria in skeletal muscle and their function decline with normal aging and in various neuromuscular diseases and in catabolic conditions such as cancer, starvation, denervation, and immobilization. Moreover, compromised mitochondrial function is also associated with metabolic disorders including type 2 diabetes mellitus. It is now clear that maintaining mitochondrial content and function in skeletal muscle is vital for sustained health throughout the lifespan. While a number of staining methods are available to study mitochondria, transmission electron microscopy (TEM) is still the most important method to study mitochondrial structure and health in skeletal muscle. It provides critical information about mitochondrial content, cristae density, organization, formation of autophagosomes, and any other abnormalities commonly observed in various disease conditions. In this article, we describe a detailed protocol for sample preparation and analysis of mouse skeletal muscle mitochondria by TEM.

Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice.

Myogenesis is a multi-step process that leads to the formation of skeletal muscle during embryonic development and repair of injured myofibers. In this process, myoblasts are the main effector cell type which fuse with each other or to injured myofibers leading to the formation of new myofibers or regeneration of skeletal muscle in adults. Many steps of myogenesis can be recapitulated through in vitro differentiation of myoblasts into myotubes. Most laboratories use immortalized myogenic cells lines that also differentiate into myotubes. Although these cell lines have been found quite useful to delineating the regulatory mechanisms of myogenesis, they often show a great degree of variability depending on the origin of the cells and culture conditions. Primary myoblasts have been suggested as the most physiologically relevant model for studying myogenesis in vitro. However, due to their low abundance in adult skeletal muscle, isolation of primary myoblasts is technically challenging. In this article, we describe an improved protocol for the isolation of primary myoblasts from adult skeletal muscle of mice. We also describe methods for their culturing and differentiation into myotubes.

Distinct roles of TRAF6 and TAK1 in the regulation of adipocyte survival, thermogenesis program, and high-fat diet-induced obesity.

Chronic low-grade inflammation, adipocyte hypertrophy, and glucose intolerance are common features of obesity and a risk factor for cancer. Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is an adaptor protein that also possesses a non-conventional E3 ubiquitin ligase activity. In response to receptor-mediated events, TRAF6 activates transforming growth factor-activated kinase 1 (TAK1), which leads to activation of the MAPK and nuclear factor-kappa B (NF-κB) signaling pathways. However, the roles of TRAF6 and TAK1 in the regulation of adipocyte function remain less understood. Here, we demonstrate that adipocyte-specific deletion of TAK1, but not TRAF6, in mice reduces the survival of adipocytes and abundance of white adipose tissue (WAT). Adipocyte-specific ablation of TAK1, but not TRAF6, increases the expression for markers of beige/brown fat in WAT. Deletion of TAK1 in WAT increases phosphorylation of AMPK, abundance of PGC-1α, non-canonical NF-κB signaling, markers of M2 macrophages, and diminishes phosphorylation of JNK and canonical NF-κB signaling. Levels of TRAF6 and enzymatic activity of TAK1 are increased in WAT of mice fed with high-fat diet (HFD). Our results demonstrate that ablation of TAK1 drastically reduces HFD-induced obesity and improves energy expenditure and glucose metabolism. In contrast, adipocyte-specific ablation of TRAF6 has a minimal effect on HFD-induced obesity. Collectively, our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades, inactivation of TAK1, but not TRAF6, regulates adipocyte survival, energy expenditure, and HFD-induced obesity in mice.