Fighting obesity by targeting factors regulating beige adipocytes.

Purpose of reviewThe current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity.Recent findingsWe outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential.SummaryThe identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders

Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice

Calorie restriction results in leanness, which is linked to metabolic conditions that favor longevity. We show here that deficiency of the triglyceride synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which promotes leanness, also extends longevity without limiting food intake. Female DGAT1-deficient mice were protected from age-related increases in body fat, tissue triglycerides, and inflammation in white adipose tissue. This protection was accompanied by increased mean and maximal life spans of ~25% and ~10%, respectively. Middle-aged Dgat1−/− mice exhibited several features associated with longevity, including decreased levels of circulating insulin growth factor 1 (IGF1) and reduced fecundity. Thus, deletion of DGAT1 in mice provides a model of leanness and extended lifespan that is independent of calorie restriction

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

Angiopoietin-like 4 (Angptl4)

Angiopoietin-like 4 (Angptl4) is a secreted protein modulating triacylglycerol homeostasis. Its transcription is induced by glucocorticoids, which act to elevate circulating Angptl4 levels during fasting. In investigating the role of Angptl4 in glucocorticoid action, we identified that in addition to its known ability to inhibit lipoprotein lipase, Angptl4 stimulates intracellular adipocyte lipolysis. Fatty acid release by murine adipocytes following fasting or treatment with glucocorticoids or catecholamines is highly Angptl4-dependent. In fact, Angptl4 can directly stimulate cAMP-dependent PKA signaling and lipolysis when added to adipocytes. Here, we detail this novel Angptl4-dependent lipolytic regulatory mechanism and discuss its physiological and therapeutic implications

Angiopoietin-like 4 (Angptl4): A glucocorticoid-dependent gatekeeper of fatty acid flux during fasting.

Angiopoietin-like 4 (Angptl4) is a secreted protein modulating triacylglycerol homeostasis. Its transcription is induced by glucocorticoids, which act to elevate circulating Angptl4 levels during fasting. In investigating the role of Angptl4 in glucocorticoid action, we identified that in addition to its known ability to inhibit lipoprotein lipase, Angptl4 stimulates intracellular adipocyte lipolysis. Fatty acid release by murine adipocytes following fasting or treatment with glucocorticoids or catecholamines is highly Angptl4-dependent. In fact, Angptl4 can directly stimulate cAMP-dependent PKA signaling and lipolysis when added to adipocytes. Here, we detail this novel Angptl4-dependent lipolytic regulatory mechanism and discuss its physiological and therapeutic implications

Fighting obesity by targeting factors regulating beige adipocytes

Purpose of reviewThe current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity.Recent findingsWe outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential.SummaryThe identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders

Lack of association between either outpatient or inpatient glycemic control and COVID-19 illness severity or mortality in patients with diabetes

Introduction To evaluate whether outpatient insulin treatment, hemoglobin A1c (HbA1c), glucose on admission, or glycemic control during hospitalization is associated with SARS-CoV-2 (COVID-19) illness severity or mortality in hospitalized patients with diabetes mellitus (DM) in a geographical region with low COVID-19 prevalence.Research design and methods A single-center retrospective study of patients hospitalized with COVID-19 from January 1 through August 31, 2020 to evaluate whether outpatient insulin use, HbA1c, glucose on admission, or average glucose during admission was associated with intensive care unit (ICU) admission, mechanical ventilation (ventilator) requirement, or mortality.Results Among 111 patients with DM, 48 (43.2%) were on outpatient insulin and the average HbA1c was 8.1% (65 mmol/mol). The average glucose on admission was 187.0±102.94 mg/dL and the average glucose during hospitalization was 173.4±39.8 mg/dL. Use of outpatient insulin, level of HbA1c, glucose on admission, or average glucose during hospitalization was not associated with ICU admission, ventilator requirement, or mortality among patients with COVID-19 and DM.Conclusions Our findings in a region with relatively low COVID-19 prevalence suggest that neither outpatient glycemic control, glucose on admission, or inpatient glycemic control is predictive of illness severity or mortality in patients with DM hospitalized with COVID-19

Lack of association between either outpatient or inpatient glycemic control and COVID-19 illness severity or mortality in patients with diabetes.

To evaluate whether outpatient insulin treatment, hemoglobin A1c (HbA1c), glucose on admission, or glycemic control during hospitalization is associated with SARS-CoV-2 (COVID-19) illness severity or mortality in hospitalized patients with diabetes mellitus (DM) in a geographical region with low COVID-19 prevalence. A single-center retrospective study of patients hospitalized with COVID-19 from January 1 through August 31, 2020 to evaluate whether outpatient insulin use, HbA1c, glucose on admission, or average glucose during admission was associated with intensive care unit (ICU) admission, mechanical ventilation (ventilator) requirement, or mortality. Among 111 patients with DM, 48 (43.2%) were on outpatient insulin and the average HbA1c was 8.1% (65 mmol/mol). The average glucose on admission was 187.0±102.94 mg/dL and the average glucose during hospitalization was 173.4±39.8 mg/dL. Use of outpatient insulin, level of HbA1c, glucose on admission, or average glucose during hospitalization was not associated with ICU admission, ventilator requirement, or mortality among patients with COVID-19 and DM. Our findings in a region with relatively low COVID-19 prevalence suggest that neither outpatient glycemic control, glucose on admission, or inpatient glycemic control is predictive of illness severity or mortality in patients with DM hospitalized with COVID-19