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Background Giant cell tumor of the tendon sheath is the most common form of giant cell tumors and is the second most common soft tissue tumor of the hand region after ganglion cyst. Magnetic resonance imaging is the diagnostic tool of choice for both diagnosis and treatment planning. The current standard treatment of choice is simple excision. The main concern about the treatment is related to the high recurrence rates. Besides incomplete excision, there is no consensus concerning the effect of other risk factors on recurrence. The literature lacks detailed reports on surgical excision of these tumors with a standardized surgical treatment and an appropriate patient follow up. The aim of this study was to investigate the recurrence rate and the associated recurrence risk factors for giant cell tumor of tendon sheath of the hand following a standardized treatment. Methods The records of patients treated for giant cell tumor of tendon sheath of the hand treated by the same hand surgeon were evaluated retrospectively. The features obtained from preoperative magnetic resonance imaging, final physical examination, patients’ age and sex, anatomical site of the tumor, relationship of the tumor with bone, joint or neurovascular structures, bone invasion, recurrence after surgery and complications like skin necrosis, digital neuropathy or limitation in range of motion were documented. Chi-square test was used to compare categorical variables. Results Fifty patient were included in the study. The average follow-up time was 84 months. Three recurrences (6%) were recorded. The only significant risk factor for the recurrence was tumor adjacency to the interphalangeal joints of the fingers other than thumb. No major or minor complications were encountered in the postoperative period. Conclusion With adequate surgical exposure and meticulous dissection provided by the magnification loupes, we were able demonstrate one of the lowest recurrence rates in the literature. Well-designed studies combining the recurrence rates of several hand surgery centers implementing a standardized treatment are needed to better demonstrate the associated risk factors for recurrence.

GDF15 has potent anti-obesity effects, but its receptor was previously unknown. GFRAL has now been identified as the receptor for GDF15, and it mediates the effects of GDF15 via central actions in the hindbrain. Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism 1 . A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer 2 . In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters 3 , suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral −/− mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4 , 5 , 6 ). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRAL AP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRAL AP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

FGF21 has gradually become a focal point in metabolic research given its intriguing and complex biology and relevance to drug discovery. Despite the large amount of accumulated data, there remains a dearth of understanding of FGF21 physiology at the molecular/whole organism level. The scaffold protein βklotho (KLB) has previously been demonstrated in vitro to function as a co-factor permitting FGF21 mediated FGF receptor activation. However, the requirement for KLB in the propagation of FGF21 action in living animals has yet to be evaluated. To answer this question, we tested FGF21 in mice with total body ablation of KLB (KLBKO) and found no detectable activity. Firstly, we demonstrate that the disruption of KLB entirely abrogates acute FGF21 signaling in adipose tissue. We go on to show that this signaling defect translates to the absence of FGF21 mediated metabolic improvements in DIO mice. Indeed, KLBKO mice are totally refractory to FGF21-induced normalization of glucose homeostasis, attenuation of dyslipidemia, elevation of energy expenditure and weight loss. The lack of FGF21-driven effects was further substantiated at the transcriptional level with no FGF21 target gene signature detectable in adipose tissue and liver of KLBKO animals. Taken together our data show that KLB is a vital component of the FGF21 in vivo signaling machinery and is critically required for FGF21 action at the whole organism level.

Amylin-based therapies are emerging as promising obesity medications. Eloralintide is a novel, selective amylin receptor agonist in development for weight management. We performed a phase 2, double blind, randomised, placebo-controlled trial with the aim of evaluating the efficacy and safety of a range of doses and dose escalation schemes of once-per-week eloralintide versus placebo in adults with obesity or overweight and had at least one weight-related comorbidity. We enrolled 263 participants from 46 research centres in the USA. Individuals aged 18–75 years with a BMI of 30 kg/m2 or higher, or a BMI of 27 kg/m2 or higher with at least one weight-related comorbidity and without type 2 diabetes were randomly assigned (2:1:1:1:2:1:2) to receive once-per-week subcutaneous injections of placebo or eloralintide at 1 mg, 3 mg, 6 mg, or 9 mg, or dose escalations of 6–9 mg or 3–9 mg for 48 weeks. The primary endpoint was percent change in bodyweight from baseline after 48 weeks of treatment. Efficacy analyses included all randomly assigned participants, and safety analyses included all participants who were randomly assigned and received at least one dose of study treatment. This study was completed on Aug 14, 2025, and is registered with ClinicalTrials.gov (NCT06230523). Between Feb 5, 2024, and Aug 14, 2025, 263 participants (mean age 49·0 years [SE 12·6], mean bodyweight 109·1 kg [22·8], BMI 39·1 kg/m2 [6·8], 204 [78%] female, and 205 [78%] White) were randomly assigned to receive eloralintide (1 mg, n=28; 3 mg, n=24; 6 mg, n=28; 9 mg, n=54; 6–9 mg, n=24; and 3–9 mg, n=52) or placebo (n=53). The efficacy analyses were based on the 263 participants randomly assigned. The mean percent change in bodyweight from baseline after 48 weeks (efficacy estimand) was –9% (1 mg, 95% CI –12·6 to –6·3), –12% (3 mg, –14·9 to –9·8), –18% (6 mg, –20·7 to –14·5), –20% (9 mg, –22·7 to –17·5), –20% (6–9 mg, –22·7 to –17·0), and –16% (3–9 mg, –18·6 to –14·1), compared with –0·4% (–2·2 to 1·4) in the placebo group. The most common adverse events with eloralintide were nausea (1 mg 11%, 3 mg 13%, 6 mg 64%, 9 mg 33%, 6–9 mg 54%, 3–9 mg 25%, and placebo 14%) and fatigue (1 mg 0%, 3 mg 13%, 6 mg 29%, 9 mg 43%, 6–9 mg 46%, 3–9 mg 21%, and placebo 12%). Eloralintide produced clinically meaningful, dose-dependent reductions in bodyweight over 48 weeks and was generally well tolerated, supporting eloralintide's potential use for obesity treatment. Eli Lilly.

Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius. Thus, BDNF mNTS neurons are required for the weight-reducing actions of both GDF15 and the GLP1RA, Exendin-4. Moreover, acute activation of BDNF mNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation and might provide a route for longer-term weight loss. The major site of action for obesity treatments based on GLP1R agonists is at the level of the brainstem where neurons share receptors for GLP-1 and GFRAL. Here, authors show two pathways downstream of GFRAL neurons, which are required for the weight-reducing actions of GDF15 and GLP1RA.

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O 2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity. Synopsis This study demonstrates that the GPR120 agonist TUG‐891 improves metabolic health by activation of brown fat. Mechanistically, TUG‐891 promotes respiration in brown adipocytes by stimulating GPR120‐dependent Ca 2+ release and mitochondrial fragmentation, thereby activating UCP1. The GPR120 agonist TUG‐891 acutely increases fat oxidation and decreases body weight and fat mass in mice. Beneficial metabolic effects of TUG‐891 are related to increased brown fat activity, reflected by an increased uptake of fatty acids by brown adipose tissue in vivo . TUG‐891 increases mitochondrial respiration in brown adipocytes in vitro , via both GPR120‐ dependent and ‐independent mechanisms. Graphical Abstract This study demonstrates that the GPR120 agonist TUG‐891 improves metabolic health by activation of brown fat. Mechanistically, TUG‐891 promotes respiration in brown adipocytes by stimulating GPR120‐dependent Ca 2+ release and mitochondrial fragmentation, thereby activating UCP1.

Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21) has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP), which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO) mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.

Activation of TGR5 via bile acids or bile acid analogs leads to the release of glucagon-like peptide-1 (GLP-1) from intestine, increases energy expenditure in brown adipose tissue, and increases gallbladder filling with bile. Here, we present compound 18, a non-bile acid agonist of TGR5 that demonstrates robust GLP-1 secretion in a mouse enteroendocrine cell line yet weak GLP-1 secretion in a human enteroendocrine cell line. Acute administration of compound 18 to mice increased GLP-1 and peptide YY (PYY) secretion, leading to a lowering of the glucose excursion in an oral glucose tolerance test (OGTT), while chronic administration led to weight loss. In addition, compound 18 showed a dose-dependent increase in gallbladder filling. Lastly, compound 18 failed to show similar pharmacological effects on GLP-1, PYY, and gallbladder filling in Tgr5 knockout mice. Together, these results demonstrate that compound 18 is a mouse-selective TGR5 agonist that induces GLP-1 and PYY secretion, and lowers the glucose excursion in an OGTT, but only at doses that simultaneously induce gallbladder filling. Overall, these data highlight the benefits and potential risks of using TGR5 agonists to treat diabetes and metabolic diseases.

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.