Site-specific analysis and functional characterization of N-linked glycosylation for β-Klotho protein.

β-Klotho (KLB), a type I transmembrane protein, serves as an obligate co-receptor determining the tissue-specific actions of endocrine fibroblast growth factors (FGFs). Despite accumulative evidence suggesting the occurrence of N-glycosylation in the KLB protein, the precise N-glycosites, glycoforms, and the impacts of N-glycosylation on the expression and function of the KLB protein remain unexplored. Employing a mass spectrometry-based approach, a total of 12 N-glycosites displaying heterogeneous site occupancy and glycoforms were identified within the extracellular region of the recombinant human KLB protein.

Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

Background And Purpose: Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome.

Chronic SIRT1 supplementation in diabetic mice improves endothelial function by suppressing oxidative stress.

Aims: Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db).

Type 1 diabetes complicated with cyclic vomiting syndrome and exogenous insulin antibody syndrome: A case report.

Every fifth individual with type 1 diabetes (T1D) suffers from an additional autoimmune disorder due to shared genetic factors and dysregulated immunity. Here we report an extremely rare case of T1D complicated with cyclic vomiting and hypoglycaemia. A 27-year-old Chinese woman with 14-year history of T1D was periodically hospitalized for severe vomiting of more than 30 times a day without apparent organic causes.

Development of a novel diagnostic assay for insulin receptor autoantibodies based on a patient with autoimmune hypoglycaemia.

Differential diagnosis of hypoglycaemia can at times be challenging for patients who appear to be well. Here we identify the case of a 66-year-old Chinese man presenting with recurrent episodes of fasting hypoglycaemia and confusion without any other manifestations. He had no personal or family history of diabetes, nor was he on any hypoglycaemic drugs.

Salivary telomere length and the risks of prediabetes and diabetes among middle-aged and older adults: findings from the Health and Retirement Study.

Aim: To assess the association of telomere length (TL) with prediabetes/diabetes and to explore the potential factors affecting TL among individuals with prediabetes/diabetes by weight status.

Methods: This study included 3,379 eligible adults (aged 45-85 years, males: 42%) from the US Health and Retirement Study in 2008. TL was assayed using quantitative PCR of saliva (T/S ratio).

FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.

Background: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms.

Fibroblast Growth Factor-Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications.

The fibroblast growth factor (FGF) family, which comprises 22 structurally related proteins, plays diverse roles in cell proliferation, differentiation, development, and metabolism. Among them, two classical members (FGF1 and FGF4) and two endocrine members (FGF19 and FGF21) are important regulators of whole-body energy homeostasis, glucose/lipid metabolism, and insulin sensitivity. Preclinical studies have consistently demonstrated the therapeutic benefits of these FGFs for the treatment of obesity, diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH).

β-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130.

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that β-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic β-cells independent of the actions of FGF21.

The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic.

Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis through a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β-klotho. Administration of FGF21 to rodents or non-human primates causes considerable pharmacological benefits on a cluster of obesity-related metabolic complications, including a reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, cardiovascular disorders and non-alcoholic steatohepatitis (NASH). However, native FGF21 is unsuitable for clinical use owing to poor pharmacokinetic and biophysical properties.

Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

Aims: Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS.

Exercise Alleviates Obesity-Induced Metabolic Dysfunction via Enhancing FGF21 Sensitivity in Adipose Tissues.

Exercise promotes adipose remodeling and improves obesity-induced metabolic disorders through mechanisms that remain obscure. Here, we identify the FGF21 signaling in adipose tissues as an obligatory molecular transducer of exercise conferring its metabolic benefits in mice. Long-term high fat diet-fed obese mice exhibit compromised effects of exogenous FGF21 on alleviation of hyperglycemia, hyperinsulinemia, and hyperlipidemia, accompanied with markedly reduced expression of FGF receptor-1 (FGFR1) and β-Klotho (KLB) in adipose tissues.

The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity.

Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11.

Branched-chain amino acids alleviate nonalcoholic steatohepatitis in rats.

Nonalcoholic steatohepatitis (NASH) is a prevalent disease in countries around the world. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine cannot be synthesized by the body and have been shown to promote muscle buildup; thus, it is logical to suggest that BCAAs can reduce fat deposition in the body. We used gonadectomized rats fed a high-fat diet to investigate the effects of BCAAs on lipid metabolism over an 8-week experimental period.