Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.

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The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21-deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis.

A group of morphology regulatory arthrosporol metabolites have been recently characterized from carnivorous fungus Arthrobotrys oligospora that can develop trapping networks to capture their prey. A combination of genetic manipulation and chemical analyses was applied to characterize the function of one polyketide synthase (PKS) gene AOL_s00215g283 in A. oligospora, which was putatively involved in the production of 6-methylsalicylic acid. High-performance liquid chromatography analysis showed that the disruption of the PKS gene not only led to the total loss of the arthrosporol A but also resulted in significant reduction in the production of secondary metabolites in the cultural broth of the mutant ΔAOL_s00215g283 strain. Interestingly, the mutant strain displayed significant increases in the trap formation and the nematicidal activity by 10 and 2 times, respectively, higher than the wild-type strain. These findings revealed a pathogenicity-related biosynthetic gene of this agriculturally important biological agent and have implications for establishment of efficient fungal biocontrol agents.

As a cellular energy sensor and regulator, adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite to increase food intake and diminishing adaptive thermogenesis in adipose tissues to reduce energy expenditure in response to food deprivation. Numerous metabolic hormones, such as leptin, adiponectin, ghrelin and insulin, exert their energy regulatory effects through hypothalamic AMPK via integration with the neural circuits. Although activation of AMPK in peripheral tissues is able to promote fatty acid oxidation and insulin sensitivity, its chronic activation in the hypothalamus causes obesity by inducing hyperphagia in both humans and rodents. In this review, we discuss the role of hypothalamic AMPK in mediating hormonal regulation of feeding and adaptive thermogenesis, and summarize the diverse underlying mechanisms by which central AMPK maintains energy homeostasis.

Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes.

Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells, and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes. The adaptor protein APPL1 potentiates insulin-stimulated Akt activation and downstream actions. However, the physiological functions of APPL2, a close homolog of APPL1, in regulating glucose metabolism remain elusive. We show that insulin-evoked plasma membrane recruitment of GLUT4 and glucose uptake are impaired by APPL2 overexpression but enhanced by APPL2 knockdown. Likewise, conditional deletion of APPL2 in skeletal muscles enhances insulin sensitivity, leading to an improvement in glucose tolerance. We identified the Rab-GTPaseactivating protein TBC1D1 as an interacting partner of APPL2. Insulin stimulates TBC1D1 phosphorylation on serine 235, leading to enhanced interaction with the BAR domain of APPL2, which in turn suppresses insulinevoked TBC1D1 phosphorylation on threonine 596 in cultured myotubes and skeletal muscle. Substitution of serine 235 with alanine diminishes APPL2-mediated inhibition on insulin-dependent TBC1D1 phosphorylation on threonine 596 and the suppressive effects of TBC1D1 on insulin-induced glucose uptake and GLUT4 translocation to the plasma membrane in cultured myotubes. Therefore, the APPL2-TBC1D1 interaction is a key step to fine tune insulin-stimulated glucose uptake by regulating the membrane recruitment of GLUT4 in skeletal muscle.

Profound loss and senescence of adipose tissues are hallmarks of advanced age, but the underlying cause and their metabolic consequences remain obscure. Proper function of the murine double minute 2 (MDM2)-p53 axis is known to prevent tumorigenesis and several metabolic diseases, yet its role in regulation of adipose tissue aging is still poorly understood. In this study, we show that the proximal p53 inhibitor MDM2 is markedly downregulated in subcutaneous white and brown adipose tissues of mice during aging. Genetic disruption of MDM2 in adipocytes triggers canonical p53-mediated apoptotic and senescent programs, leading to age-dependent lipodystrophy and its associated metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, hyperlipidemia, and energy imbalance. Surprisingly, this lipodystrophy mouse model also displays premature loss of physiological integrity, including impaired exercise capacity, multiple organ senescence, and shorter life span. Transplantation of subcutaneous fat rejuvenates the metabolic health of this aging-like lipodystrophy mouse model. Furthermore, senescence-associated secretory factors from MDM2-null adipocytes impede adipocyte progenitor differentiation via a non-cell-autonomous manner. Our findings suggest that tight regulation of the MDM2-p53 axis in adipocytes is required for adipose tissue dynamics and metabolic health during the aging process.