A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

Predictors of Mortality in Hypercalcemia of Advanced Chronic Liver Disease.

OBJECTIVE: Hypercalcemia is sometimes observed in patients with cirrhosis, but very little is known about the epidemiology in patients with hypercalcemia of chronic liver disease (HCLD) or how its presence may modulate the overall mortality risk. We assessed the associations between the clinical and laboratory characteristics of patients with HCLD with 90-day mortality. METHODS: A systematic search of the medical records at our institution over a 10-year period was performed to retrospectively identify subjects with HCLD during inpatient admission. Univariate and multivariable regression analyses were performed to detect the risk factors for all-cause 90-day mortality. RESULTS: Thirty-eight subjects with HCLD were identified using stringent inclusion and exclusion criteria to exclude individuals with other secondary causes of hypercalcemia. A total of 35 subjects had 90-day vital status available, which revealed 40% mortality. The model for end-stage liver disease sodium score and duration of inpatient hypercalcemia were positively associated with mortality with respective odds ratios of 1.23 (95% CI, 1.06-3.23) and 1.24 (95% CI, 1.04-1.49) in a univariate regression model and 1.30 (95% CI, 1.04-1.62) and 1.33 (95% CI, 1.04-1.71) in a multivariable regression model. The admission and peak serum calcium levels were not associated with mortality. Only 6 subjects received bisphosphonates or calcitonin during their admission, limiting our ability to assess the impact of treatment on outcomes. CONCLUSION: In patients admitted to the hospital with HCLD, the duration of hypercalcemia was positively associated with 90-day mortality, providing a potential interventional target to reduce mortality in this high-risk population. Studies to validate the utility of treating hypercalcemia are required.

USE OF THE FREE THYROXINE INDEX TO REFINE THE LOWER LIMIT OF A FREE THYROXINE IMMUNOASSAY FOR DETECTION OF SECONDARY HYPOTHYROIDISM.

OBJECTIVE: To determine the utility of measuring free T4 index (FT4I) in patients with low free T4 (FT4) levels using immunoassay and normal thyroid-stimulating hormone for the evaluation of secondary hypothyroidism. METHODS: We performed a retrospective medical chart review of patients seen at a single institution as outpatients who had a simultaneously normal thyroid-stimulating hormone level, low FT4 level, and any FT4I measured between June 2014 and October 2016. Demographic, laboratory, and imaging data were collected. Using FT4I as the reference for diagnosis of hypothyroidism, the sensitivity and specificity of the FT4 immunoassay's lower-limit thresholds were determined. Within each threshold group, available brain imaging and biochemical evaluation were categorized according to the presence or absence of pituitary disease. RESULTS: A total of 155 sets of result pairs (FT4 and FT4I) performed on 118 subjects were analyzed. The lower limit of a normal FT4 level by immunoassay at this institution was 0.93 ng/dL, though all pairs with FT4 ≥0.89 ng/dL had a normal FT4I. All pairs with FT4 ≤0.67 ng/dL had a low FT4I. No pituitary macroadenomas were identified in any subject, though the rates of pituitary imaging in this patient sample were low. CONCLUSION: Patients with a borderline low FT4 level by immunoassay often have normal FT4I. In such patients at our center, significant structural and biochemical pituitary pathology was uncommon.

Glycemic Gap Predicts Mortality in a Large Multicenter Cohort Hospitalized With COVID-19.

CONTEXT: Diabetes or hyperglycemia at admission are established risk factors for adverse outcomes during hospitalization for COVID-19, but the impact of prior glycemic control is not clear. OBJECTIVE: We aimed to examine the associations between admission variables, including glycemic gap, and adverse clinical outcomes in patients hospitalized with COVID-19 infection. METHODS: We examined the relationship between clinical predictors, including acute and chronic glycemia, and clinical outcomes, including intensive care unit (ICU) admission, mechanical ventilation (MV), and mortality among 1786 individuals with diabetes or hyperglycemia (glucose > 10 mmol/L twice in 24 hours) who were admitted from March 2020 through February 2021 with COVID-19 infection at 5 university hospitals in the eastern United States. RESULTS: The cohort was 51.3% male, 53.3% White, 18.8% Black, 29.0% Hispanic, with age = 65.6 ± 14.4 years, BMI = 31.5 ± 7.9 kg/m2, glucose = 12.0 ± 7.5 mmol/L [216 ± 135 mg/dL], and HbA1c = 8.07% ± 2.25%. During hospitalization, 38.9% were admitted to the ICU, 22.9% received MV, and 10.6% died. Age (P < 0.001) and admission glucose (P = 0.014) but not HbA1c were associated with increased risk of mortality. Glycemic gap, defined as admission glucose minus estimated average glucose based on HbA1c, was a stronger predictor of mortality than either admission glucose or HbA1c alone (OR = 1.040 [95% CI: 1.019, 1.061] per mmol/L, P < 0.001). In an adjusted multivariable model, glycemic gap, age, BMI, and diabetic ketoacidosis on admission were associated with increased mortality, while higher estimated glomerular filtration rate (eGFR) and use of any diabetes medication were associated with lower mortality (P < 0.001). CONCLUSION: Relative hyperglycemia, as measured by the admission glycemic gap, is an important marker of mortality risk in COVID-19.

Crosstalk Between Adipose and Lymphatics in Health and Disease.

Adipose tissue, once thought to be an inert receptacle for energy storage, is now recognized as a complex tissue with multiple resident cell populations that actively collaborate in response to diverse local and systemic metabolic, thermal, and inflammatory signals. A key participant in adipose tissue homeostasis that has only recently captured broad scientific attention is the lymphatic vasculature. The lymphatic system's role in lipid trafficking and mediating inflammation makes it a natural partner in regulating adipose tissue, and evidence supporting a bidirectional relationship between lymphatics and adipose tissue has accumulated in recent years. Obesity is now understood to impair lymphatic function, whereas altered lymphatic function results in aberrant adipose tissue deposition, though the molecular mechanisms governing these phenomena have yet to be fully elucidated. We will review our current understanding of the relationship between adipose tissue and the lymphatic system here, focusing on known mechanisms of lymphatic-adipose crosstalk.

Lipolysis-derived linoleic acid drives beige fat progenitor cell proliferation.

De novo beige adipocyte biogenesis involves the proliferation of progenitor cells in white adipose tissue (WAT); however, what regulates this process remains unclear. Here, we report that in mouse models but also in human tissues, WAT lipolysis-derived linoleic acid triggers beige progenitor cell proliferation following cold acclimation, ß3-adrenoceptor activation, and burn injury. A subset of adipocyte progenitors, as marked by cell surface markers PDGFRα or Sca1 and CD81, harbored cristae-rich mitochondria and actively imported linoleic acid via a fatty acid transporter CD36. Linoleic acid not only was oxidized as fuel in the mitochondria but also was utilized for the synthesis of arachidonic acid-derived signaling entities such as prostaglandin D2. Oral supplementation of linoleic acid was sufficient to stimulate beige progenitor cell proliferation, even under thermoneutral conditions, in a CD36-dependent manner. Together, this study provides mechanistic insights into how diverse pathophysiological stimuli, such as cold and burn injury, promote de novo beige fat biogenesis.

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.

Mesothelial cells are not a source of adipocytes in mice.

Visceral adipose tissue (VAT) depots are associated with the adverse metabolic consequences of obesity, such as insulin resistance. The developmental origin of VAT depots and the identity and regulation of adipocyte progenitor cells have been active areas of investigation. In recent years, a paradigm of mesothelial cells as a source of VAT adipocyte progenitor cells has emerged based on lineage tracing studies using the Wilms' tumor gene, Wt1, as a marker for cells of mesothelial origin. Here, we show that Wt1 expression in adipose tissue is not limited to the mesothelium but is also expressed by a distinct preadipocyte population in mice and humans. We identify keratin 19 (Krt19) as a highly specific marker for the adult mouse mesothelium and demonstrate that Krt19-expressing mesothelial cells do not differentiate into visceral adipocytes. These results contradict the assertion that the VAT mesothelium can serve as a source of adipocytes.

Prolonged glucosuria and relapse of diabetic ketoacidosis related to SGLT2-inhibitor therapy.

SGLT2 inhibitors (SGLT2i) are glucose-lowering medications which increase the renal threshold for glucose reabsorption and promote glucosuria. Treatment with these agents raises serum ketone levels, and cases of diabetic ketoacidosis (DKA) during therapy have been reported. The duration of glucosuria and inpatient course of SGLT2i-related DKA, however, is not well-characterized. We report 11 inpatient cases of SGLT2i-related DKA, including a subset of patients who experienced prolonged glucosuria and relapse of DKA during their hospitalization.

Efficacy, safety, and patient acceptability of Technosphere inhaled insulin for people with diabetes: a systematic review and meta-analysis.

BACKGROUND: Technosphere inhaled insulin is a non-invasive alternative to subcutaneous injectable insulin for adults with type 1 or 2 diabetes. In this systematic review and meta-analysis of randomised controlled trials, we aimed to establish the efficacy, safety, and patient acceptability of Technosphere inhaled insulin in patients with diabetes. METHODS: We searched MEDLINE, the Cochrane Central Register of Controlled Clinical Trials, ClinicalTrials.gov, and relevant US regulatory documents for reports of randomised trials published in English up to May 30, 2015, that compared mealtime Technosphere inhaled insulin with placebo, subcutaneous insulin, or oral antidiabetic drugs in people with type 1 or type 2 diabetes. Two reviewers independently extracted data for outcomes of interest and risk of bias. Endpoints included changes in HbA1c concentration and bodyweight, and safety outcomes, including severe hypoglycaemia and pulmonary toxicity. When three or more studies provided relevant data, we did a meta-analysis for the outcome using a profile-likelihood random-effects model. FINDINGS: 13 trials met the inclusion criteria for qualitative systematic review; 12 met the inclusion criteria for quantitative meta-analysis (n=5273; age range 18-80). HbA1c decrease from baseline was greater with subcutaneous insulin than with Technosphere inhaled insulin (net difference 0·16%, 95% CI 0·06-0·25; eight trials). However, inhaled insulin was associated with less weight gain (net difference -1·1 kg, -2·1 to -1·6; three trials) and a smaller risk of severe hypoglycaemia (odds ratio 0·61, 95% CI 0·35-0·92; five trials). Incidence of mild transient cough was increased in people allocated to inhaled insulin (odds ratio 7·82, 6·14-10·15; seven trials) compared with those allocated to active comparator groups, as was the decrease in forced expiratory volume in 1 s (net difference -0·038 L, -0·049 to -0·026; five trials). Quality of life and overall patient satisfaction did not differ significantly between inhaled insulin groups and active comparator groups (no numerical estimate). INTERPRETATION: Glycaemic efficacy of Technosphere inhaled insulin is lower than that of subcutaneous insulin, but inhaled insulin has a lower risk of severe hypoglycaemia and weight gain. Long-term outcomes and safety with Technosphere insulin should be further investigated. Until further data for safety become available, Technosphere inhaled insulin should be reserved for healthy adults with diabetes who do not have pulmonary disease and who would otherwise delay initiating or intensifying insulin therapy because they are unwilling or unable to use injectable insulin. FUNDING: None.