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The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

The cellular mechanisms underlying a greater risk of cardiometabolic disease in adult offspring exposed to maternal obesity are not known. Our prior work found reduced skeletal muscle mitochondrial metabolism and insulin sensitivity in offspring exposed to maternal (m) Western-style diet (WD), even when weaned onto a control diet (CD) in Japanese macaques. Here, we performed multiple comparisons of differentially expressed (DE) genes in skeletal muscle from lean juvenile offspring to test hypotheses specific to (1) the lasting effects of maternal diet composition and/or maternal adiposity on gene expression and (2) the transcriptional response to a chronic postweaning (pw)WD with and without prior exposure to mWD. Overall, we identified maternal (m)WD, and not maternal adiposity, as a principal driver of DE in offspring muscle even years after exposure with few differences observed in patterns of DE between offspring of lean vs. obese mWD dams. Transcriptional response to the pwWD was robust in mCD offspring but blunted by mWD, particularly in males, suggesting a potential priming of gene expression. KEGG enrichment analysis and assessment of top DE genes identified changes in key pathways associated with dysregulated metabolism and RNA processing. We conclude that mWD has a significant and lasting impact on offspring gene expression which likely contributes to observed skeletal muscle insulin resistance and metabolic dysregulation in these offspring.

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing translating ribosome affinity purification with RNA-sequencing (TRAP-seq) data with single-nucleus RNA-sequencing (snRNA-seq) data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of six major genetically and anatomically differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously suggested unique roles for leptin receptor ( Lepr )-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.

ABSTRACT Obesity and its co‐morbidities are increasing as public health challenges worldwide. Non‐human primates with their similarity to human physiology and susceptibility to metabolic diseases represent a valuable, clinically translational animal model in metabolic disease research. We aimed to characterize the impact of long‐term high fat, high carbohydrate and high cholesterol diet (FFC) feeding on the host metabolism and gut microbiota in male Cynomolgus Macaque monkeys. Twenty‐three male Cynomolgus Macaque (Macaca fascicularis) monkeys were housed indoors from the age of approximately 2 years and fed a FFC diet for 4.5 years. Diabetes and obesity‐related parameters, gut microbiota composition, circulating bile acids and short chain fatty acids were characterized. The FFC diet induced obesity with elevated levels of trunk fat (TF%) of 39.7% ± 14.9%. There was a significant association between TF% and fasting insulin, HbA1c%, triglyceride levels, and the ratio of glycine‐ to taurine‐conjugated bile acids. TF% was associated with changes in the fecal microbiota composition, predominantly driven by Coprococcus spp. and members of the families Enterobacteriaceae and Lactobacillaceae, similar to observations in humans with obesity. It is concluded that the FFC diet induced obesity, hypertriglyceridemia, impaired insulin sensitivity and dysregulated glucose metabolism. Microbial diversity did not differ between obesity states described as four TF% quartiles, but the fecal microbiota composition was significantly associated with the TF% driven by Coprococcus spp. and members of the families Enterobacteriaceae and Lactobacillaceae. Whether the gut microbiota changes were a cause or consequence of the obese state and impaired glucose metabolism remains to be studied.

Background We and others have previously shown that alterations in the mammalian gut microbiome are associated with diet, notably early life exposure to a maternal high fat diet (HFD). Here, we aimed to further these studies by examining alterations in the gut microbiome of juvenile Japanese macaques ( Macaca fuscata ) that were exposed to a maternal HFD, weaned onto a control diet, and later supplemented with a synbiotic comprised of psyllium seed and Enterococcus and Lactobacillus species. Results Eighteen month old offspring ( n  = 7) of 36% HFD fed dams were fed a control (14% fat) diet post weaning, then were synbiotic supplemented for 75 days and longitudinal stool and serum samples were obtained. All stool samples were subjected to 16S rRNA metagenomic sequencing, and microbiome profiles and serum lipids and triglycerides were compared to untreated, healthy age matched and diet matched controls ( n  = 7). Overall, 16S-based metagenomic analysis revealed that supplementation exerted minimal alterations to the gut microbiome including transient increased abundance of Lactobacillus species and decreased abundance of few bacterial genera, including Faecalibacterium and Anaerovibrio . However, serum lipid analysis revealed significant decreases in triglycerides, cholesterol, and LDL ( p  < 0.05). Nevertheless, supplemented juveniles challenged 4 months later were not protected from HFD-induced gut dysbiosis. Conclusions Synbiotic supplementation is temporally associated with alterations in the gut microbiome and host lipid profiles of juvenile Japanese macaques that were previously exposed to a maternal HFD. Despite these presumptive temporal benefits, a protective effect against later HFD-challenge gut dysbiosis was not observed.

Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving the life expectancy of people living with HIV; however, they also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the effect of preexisting metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

A maternal Western-style diet (WSD) is associated with poor reproductive outcomes, but whether this is from the diet itself or underlying metabolic dysfunction is unknown. Here, we performed a longitudinal study using regularly cycling female rhesus macaques (n = 10) that underwent 2 consecutive in vitro fertilization (IVF) cycles, one while consuming a low-fat diet and another 6-8 months after consuming a high-fat WSD. Metabolic data were collected from the females prior to each IVF cycle. Follicular fluid (FF) and oocytes were assessed for cytokine/steroid levels and IVF potential, respectively. Although transition to a WSD led to weight gain and increased body fat, no difference in insulin levels was observed. A significant decrease in IL-1RA concentration and the ratio of cortisol/cortisone was detected in FF after WSD intake. Despite an increased probability of isolating mature oocytes, a 44% reduction in blastocyst number was observed with WSD consumption, and time-lapse imaging revealed delayed mitotic timing and multipolar divisions. RNA sequencing of blastocysts demonstrated dysregulation of genes involved in RNA binding, protein channel activity, mitochondrial function and pluripotency versus cell differentiation after WSD consumption. Thus, short-term WSD consumption promotes a proinflammatory intrafollicular microenvironment that is associated with impaired preimplantation development in the absence of large-scale metabolic changes.

Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient’s immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 ( B2M −/− CIITA −/− CD47 + ). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected. A genetic method to block immune rejection of allogeneic cells is validated in monkeys.