David Holmes

Obesity: Medicinal mushroom reduces obesity by modulating microbiota

by modulating the composition of the gut microbiota. The findings raise hope that in the future, this mushroom could be used as a prebiotic to combat obesity and obesity-related metabolic disorders. The researchers prepared a water extract of Ganoderma lucidum mycelium (WEGL), which was isolated and cultured using an advanced biofermentation process, and administered it to high-fat diet (HFD)-fed mice daily for 2 months by oral gavage. Supplementation with WEGL dose-dependently reduced weight gain and both epididymal and subcutaneous fat accumulation in HFD-fed mice compared with untreated controls. Inflammation and insulin resistance were also reduced in WEGL-treated HFD-fed mice compared with untreated controls. As obesity alters the composition of the gut microbiota in both people and HFD-fed mice, the researchers examined whether WEGL treatment could modulate the gut microbiota. Bacterial 16S RNA sequencing of faecal samples revealed that WEGL treatment reduced the ratio of Firmicutes to Bacteroidetes and levels OBESITY

Metabolism: Fasting induces FGF21 in humans.

levels of FGF21 are markedly increased by fasting in humans and are part of the late stages of the body’s adaptive response to starvation — a protective mechanism that evolved to aid survival in periods of famine. In contrast to mice, in which levels of FGF21 are rapidly increased by fasting, previous studies in humans have either demonstrated no increase or only a modest increase in levels of FGF21 in response to fasting. “We felt that a conclusive fasting study needed to be performed in healthy individuals to definitively answer whether FGF21 was a fasting-induced hormone in humans and to understand what happens to levels of FGF21 during fasting,” explains joint-lead investigator Pouneh Fazeli. The researchers serially measured levels of FGF21 in 11 healthy male and female volunteers (aged 22.4–48.3 years; BMI 22.7–29.3 kg/m) during a 10-day fast. Although decreased in the early phase of the fast, levels of FGF21 at day 10 were fourfold higher than those at day 0. Induction of FGF21 was associated with decreased thermogenesis of brown adipose tissue (measured by PET/MRI) and reduced levels of adiponectin, and occurred after the ketogenic response. Furthermore, FGF21 induction closely correlated with the release of markers of tissue breakdown (serum transaminases) and with weight loss. “Our study definitively establishes FGF21 as a fasting-induced hormone in humans,” states co-lead investigator Matthew Steinhauser. “By measuring FGF21 levels serially over a full 10-day fast in healthy volunteers, we now know why previous studies in humans reported inconsistent results, namely that FGF21 is induced in the majority of individuals, but only after a long-term fast.” On the basis of beneficial metabolic effects elicited by FGF21 treatment in mice (prevention of diet-induced obesity and improved glucose tolerance), FGF21 mimetics are being developed to treat metabolic diseases such as type 2 diabetes mellitus. “Our finding that the function of FGF21 might be highly dependent on an individual’s nutritional status could be an important consideration as these potential drugs are developed,” cautions Steinhauser.

Gut microbiota: Antidiabetic drug treatment confounds gut dysbiosis associated with type 2 diabetes mellitus.

Gut microbiota: Antidiabetic drug treatment confounds gut dysbiosis associated with type 2 diabetes mellitus

Metabolism: WAT browning—key feature of cancer-associated cachexia

Two new studies highlight the important role of white adipose tissue (WAT) browning in the development and progression of cancer-associated cachexia (CAC)—a wasting disorder of adipose tissue and skeletal muscle. In the first study, researchers led by Erwin Wagner observed a phenotypic switch from WAT to brown adipose tissue and increased energy expenditure, which preceded skeletal muscle atrophy, in many mouse models of CAC. “This is the first time that WAT browning has been recognized as being responsible for the pathogenesis of a disease,” explains Wagner. “Until now, only the beneficial effects of WAT browning in the context of obesity and diabetes were known.” The researchers found increased levels of IL-6—a proinflammatory cytokine—in the blood of cachectic mice. Blocking IL-6 release in CAC mice rescued the cachectic phenotype. “Our data in animal models show that anti-inflammatory drugs are beneficial to ameliorate cachexia, METABOLISM

Metabolism: kisspeptin signalling linked to obesity.

New research in mice shows that targeted inactivation of the kisspeptin receptor gene (Kiss1r) results in obesity and a diabetic phenotype. The findings demonstrate novel metabolic roles of kisspeptin signalling that might be relevant to obesity, diabetes and broader metabolic dysfunction in humans. The neuropeptide kisspeptin stimulates gonadotropin-releasing hormone neurons in the brain—a key step in activation of the reproductive axis. Evidence of widespread expression of kisspeptin and its receptor in metabolic tissues, such as fat, liver and pancreas, led the researchers to study the energetic and metabolic phenotype of mice deficient in kisspeptin signalling. Kiss1r–/– female mice exhibited increased body weight, adiposity and leptin levels, and reduced glucose tolerance, compared with wild-type sex-matched littermates; conversely, male Kiss1r–/– mice had normal body weight and glucose tolerance. Female transgenic mice consumed less food than METABOLISM

Diabetes: SDF-1 dysregulation mediates diabetic stem cell mobilopathy.

Two new studies highlight the potential of targeting bone marrow macrophages (BMMΦ) to prevent vascular complications of diabetes mellitus. “The results have profound implications for the care of patients with diabetes mellitus who have haematological disorders and for our understanding of how the bone marrow works and how it is affected by diabetes mellitus,” explains lead investigator Gian Paolo Fadini. Diabetes mellitus damages the bone marrow microenvironment and impairs mobilization of bone marrow stem cells (BMSCs) into the peripheral blood. This type of diabetic complication, called stem cell mobilopathy, can amplify multiorgan complications, as bone marrow is the source of vascular regenerative cells. Previous studies showed that diabetes mellitus causes polarization of BMMΦ to a proinflammatory phenotype and that these macrophages promote BMSC retention via induction of stromal cell-derived factor 1 (SDF-1, also known as CXCL12). In the first study, the researchers investigated whether BMMΦ contribute to diabetic stem cell mobilopathy. Patients with type 1 diabetes mellitus had significantly more proinflammatory (M1) macrophages than matched control patients, and streptozotocininduced diabetic mice had more CD169+ BMMΦ (with stem cell retaining activity) than wild-type littermates. Depletion of these macrophages with clodronate liposomes restored stem cell mobilization in diabetic mice; furthermore, conditioned media from human M1, but not M0 or M2, macrophages induced SDF-1 expression in human BMSCs, which indicates that these macrophages secrete a soluble factor that prevents stem cell mobilization via induction of SDF-1. In silico data mining and in vitro validation identified oncostatin M (OSM) as the soluble mediator; neutralization of OSM blocked SDF-1 induction, improved stem cell mobilization and homing, and vascular recovery in diabetic mice. Moreover, levels of OSM were higher in patients with diabetes mellitus than in control patients and correlated with the extent of stem cell mobilization. In the second study, the researchers investigated whether the SDF-1 receptor (CXCR4) antagonist plerixafor is more effective than G-CSF in mobilizing stem cells in patients with diabetes mellitus. In a prospective study, plerixafor was equally able to induce stem cell mobilization in patients with and without diabetes mellitus. Whereas in two retrospective studies, diabetes mellitus was associated with greater stem cell mobilization in patients who received plerixafor + G-CSF than in those receiving just G-CSF. “Overall, these data consistently suggest that maladaptive SDF-1 regulation is responsible for impaired stem cell mobilization in diabetes mellitus,” explains Fadini. “Whether targeting this abnormality will translate into vascular protection in humans needs further investigation.”

Neuroendocrinology: Leptin attenuates HPA-axis activation and stress responses.

The satiety hormone leptin antagonizes the activity of neurons expressing hypocretin (Hcrt, also known as orexin) and Hcrt-mediated stress responses, according to new research in mice. The findings demonstrate a link between imbalances in energy homeostasis and dysregulation of the hypothalamic– pituitary–adrenal (HPA) axis and stress. Previously, Luis de Lecea and colleagues demonstrated that acute optogenetic stimulation of Hcrt-expressing neurons increased the probability of arousal, which suggested that Hcrt-mediated stress could be a consequence of overactivation of the normal arousal response. In the current study, the researchers established the conditions required to induce Hcrt neurons in the lateral hypothalamus to release corticosterone—a physiological hallmark of the stress response. Leptin, acting locally within the lateral hypothalamus, suppressed excitation NEUROENDOCRINOLOGY

Bone: Key role for S1P in bone remodelling.

New research published in Nature Communications shows that the hormone calcitonin negatively regulates bone formation by inhibiting the release of the anabolic bone factor sphingosine 1‐phosphate (S1P) from osteoclasts. The findings highlight the existence of a novel mechanism involved in bone remodelling. Although calcitonin pharmacologically inhibits bone resorption, its physiological role is uncertain as calcitonin‐deficient mice have increased bone formation even though the calcitonin receptor (CT‐R) is not expressed on osteoblasts. “To clarify the cellular and molecular mechanisms of calcitonin action in bone remodelling, we generated a mouse model that enabled cell‐type‐specific inactivation of CT‐R,” explains lead investigator Michael Amling. Transgenic mice with ubiquitous or osteoclast‐specific inactivation of CT‐R had both increased trabecular bone mass and bone formation, in comparison with wild‐type littermates. Mechanistic insight into how CT‐R in osteoclasts regulates bone formation was provided by transcriptional profiling of calcitonin‐ treated osteoclasts isolated from CT‐R‐ deficient and wild‐type mice. Of the differentially expressed genes identified, Spns2 (which encodes a transporter for S1P) was found to be negatively regulated by calcitonin in wild‐type osteoclasts. This finding, together with the increased levels of S1P present in CT‐R‐deficient mice, suggests that calcitonin regulation of bone formation is mediated via S1P release from osteoclasts. Further observations showed that mice deficient in both CT‐R and the S1P receptor 3 (S1PR3) had a normal skeletal phenotype. The potential clinical implications of this finding were further supported by the observation that a nonselective S1PR agonist induced bone formation in wild‐type mice but not in S1PR3‐deficient mice. “S1PR3 agonists could potentially be used to treat patients with bone loss, such as those with osteoporosis,” speculates Amling. “It is important to note that S1PR3‐deficient mice displayed no obvious abnormalities in other organs, which indicates that drugs targeting S1PR3 could potentially have minimal adverse effects,” he adds.

Thyroid gland: Unlocking the potential of thyroid autoantibodies

Two new studies highlight the value of thyroid autoantibodies in predicting both the risk of developing differentiated thyroid cancer (DTC) and the long-term outcome of patients with DTC. Thyroid autoantibodies are characteristic of Hashimoto thyroiditis, and are associated with lymphocytic infiltration and destruction of the thyroid gland, leading to hypothyroidism. However, the relationship between Hashimoto thyroiditis and DTC is controversial. In particular, debate is ongoing as to whether the inflammation in Hashimoto thyroiditis is a cause or consequence of DTC. Additionally, the effect of inflammation on the outcome of patients with DTC is uncertain. In the first study, researchers led by Juan Carlos Jaume analysed the medical records of 2,811 patients referred for thyroid surgery, of whom 582 had a pathology-confirmed diagnosis of Hashimoto thyroiditis. 365 patients with Hashimoto thyroiditis were euthyroid; the hypothyroid patients were stratified by the replacement dose of levothyroxine administered (low, middle or high). Overall, the relative risk of DTC was significantly increased only in euthyroid THYROID GLAND

Biomarkers: Sclerostin levels linked to CKD outcomes.

Serum levels of the anti-anabolic bone protein sclerostin are associated with an increased risk of cardiovascular events and mortality in patients with chronic kidney disease (CKD), according to a new study. Alterations in mineral homeostasis that accompany worsening of kidney function—leading to CKD–mineral and bone disorder syndrome—are an important contributor to CKDassociated cardiovascular disease and mortality. As serum levels of sclerostin have previously been shown to positively correlate with the progression of CKD, the researchers investigated the potential of using sclerostin levels to predict future cardiovascular events and mortality in a population with CKD not undergoing dialysis. Serum sclerostin levels were significantly higher in 173 patients with CKD (stages 3–5) than in 47 control individuals (without CKD, diabetes or hypertension) and increased with the severity of CKD. When patients with BIOMARKERS