Platelet-derived lipids promote insulin secretion of pancreatic ß cells.

Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic ß cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from ß cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting ß cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on ß cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.

Targeting ERK3/MK5 complex for treatment of obesity and diabetes.

Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored. Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes. Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2.

Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142+ cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.

Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity.

Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application.

BACKGROUND: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic. SCOPE OF REVIEW: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies. MAJOR CONCLUSIONS: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood.

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation.

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that ß-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.

The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling.

Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.

Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity.

Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the ß3-adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)-α- and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.

The roles of peripheral serotonin in metabolic homeostasis.

Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis.

Molecular pathways reflecting poor intrauterine growth are found in Wharton's jelly-derived mesenchymal stem cells.

STUDY QUESTION: Are molecular pathways reflecting the biology of small for gestational age (SGA) neonates preserved in umbilical cord-derived mesenchymal stem cells (MSCs)? SUMMARY ANSWER: MSCs from SGA newborns were found to express an altered EGR-1-dependent gene network involved in the regulation of cell proliferation and oxidative stress. WHAT IS KNOWN ALREADY: Individuals with suboptimal intrauterine development are at greater risk of metabolic diseases such as type II diabetes, obesity and cardiovascular disease. STUDY DESIGN, SIZE, DURATION: Umbilical cords (n = 283) from the GUSTO (growing up in Singapore towards healthy outcomes) birth cohort study, and primary MSC isolates established from SGA and matched control cases (n = 6 per group), were subjected to gene expression analysis and candidate genes were studied for functional validation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Umbilical cord specimens were derived from babies born at the National University Hospital (NUH) in Singapore. Local ethical approval was obtained. MSC isolates were established in Wharton's jelly and molecular analysis was conducted by gene expression microarrays and RT-PCR. Cells from SGA and control groups were compared in the presence and absence of insulin and candidate gene function was studied via siRNA-mediated gene knockdown and over-expression experiments in MSCs. MAIN RESULTS AND THE ROLE OF CHANCE: Using repeated measure ANOVAs, proliferation rates of MSCs isolated from SGA neonates were found to be significantly increased (P < 0.01). In the absence of insulin, EGR-1 levels were found to be significantly reduced in the group of SGA-derived MSCs, whereas EGR-1 expression was found to be up-regulated in the same group in the presence of insulin (P < 0.01). EGR-1 was found to induce expression of COX-2 in the SGA group (P < 0.01) and both, EGR-1 and COX-2 stimulated glucose uptake in MSCs (P < 0.01). EGR-1 and COX-2 levels were associated in whole umbilical cords (n = 283, P < 0.01) and EGR-1 positively correlated with abdominal circumference and birthweight (n = 91, P < 0.01 and n = 91, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: Cell models may not entirely reflect the physiology of the host and patient follow-up studies will be necessary for further clinical validation. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that Wharton's jelly-derived MSCs are useful in identifying pathways specific for fetal growth restriction. STUDY FUNDING/COMPETING INTERESTS: This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008'. SICS Investigators are supported through the Agency for Science Technology and Research (A*STAR) funding. No potential conflicts of interest relevant to this article were reported.