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Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5‐year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long‐chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long‐chain fatty acids into fatty acyl‐CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose‐ and time‐dependent manner. RNA‐sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma. Triacsin C inhibition of the acyl‐CoA synthetase long chain (ACSL) family decreases multiple myeloma cell survival, proliferation, mitochondrial respiration, and membrane potential. Made with Biorender.com.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr . The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the β-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis. An antibody against the pituitary hormone Fsh reduces adiposity and increases thermogenesis in ovariectomized mice or mice fed a high-fat diet. Fat-reducing antibody Menopause is associated with bone loss and enhanced build-up of abdominal fat. Previously, Mone Zaidi and colleagues showed that an antibody against the pituitary hormone Fsh increases bone mass in mice. In this paper, they show that this antibody also reduces fatty tissue in mice that have had their ovaries removed or mice on a high fat diet. The anti-obesity effect is accompanied by increases in UCP1 expression and thermogenesis in brown and beige fat, increased whole-body oxygen consumption rate and physical activity. The authors suggest that these findings could open up opportunities for combined treatment of obesity and osteoporosis.

Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology. To evaluate the potential contribution of aberrant thyroid hormone status to the epigenetic inheritance of neurological phenotypes, we examined genetically normal F2 generation descendants of mice that were developmentally overexposed to thyroid hormone due to a Dio3 mutation. Hypothalamic gene expression profiling in postnatal day 15 F2 descendants on the paternal lineage of ancestral male and female T3-overexposed mice revealed, respectively, 1089 and 1549 differentially expressed genes. A large number of them, 675 genes, were common to both sets, suggesting comparable epigenetic effects of thyroid hormone on both the male and female ancestral germ lines. Oligodendrocyte- and neuron-specific genes were strongly overrepresented among genes showing, respectively, increased and decreased expression. Altered gene expression extended to other brain regions and was associated in adulthood with decreased anxiety-like behavior, increased marble burying and reduced physical activity. The sperm of T3-overexposed male ancestors revealed significant hypomethylation of CpG islands associated with the promoters of genes involved in the early development of the central nervous system. Some of them were candidates for neurodevelopmental disorders in humans including Nrg3, Nrxn1, Gabrb3, Gabra5, Apba2, Grik3, Reln, Nsd1, Pcdh8, En1, and Elavl2. Thus, developmental levels of thyroid hormone influence the epigenetic information of the germ line, disproportionately affecting genes with critical roles in early brain development, and leading in future generations to disease-relevant alterations in postnatal brain gene expression and adult behavior.

Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner. Lay Summary Sodium glucose cotransporter 2 inhibitors, like canagliflozin (CANA), are used to treat type II diabetes, but have recently been approved for treatment of cardiovascular and renovascular disease. There is concern that CANA may increase the risk of bone fracture in diabetic patients, but the findings are contradictory. Limited studies have examined skeletal health following CANA in nondiabetic models. In this study, we sought to determine the effects of an intermediate period of CANA treatment on male and female mice of varying skeletal maturity. We found that 6 months of CANA improved bone morphology in nondiabetic mice. Females gained more morphological benefits from CANA treatment than males. Bone marrow adiposity, which is often correlated with lower bone mass, was decreased by CANA treatment in females but not males. We also compared the age at initiation of CANA treatment; animals beginning treatment prior to skeletal maturity had similar responses to those treated in adulthood. In summary, intermediate periods of CANA improved bone morphology but reduced osteoblast and bone marrow adipocyte number. Graphical Abstract Graphical Abstract

Summary Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. Introduction Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18–23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. Methods Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. Results C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. Conclusions Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies utilizing mice as preclinical models for osteoporosis.

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. The Cancer Dependency Map data suggested that ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show that inhibition of ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) causes apoptosis and decreases proliferation in a dose- and time-dependent manner. RNA-seq of MM.1S cells treated with TriC for 24 h showed a significant enrichment in apoptosis, ferroptosis, and ER stress. Proteomics of MM.1S cells treated with TriC for 48 h revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest, consistent with our observations of decreased mitochondrial membrane potential and increased mitochondrial superoxide levels. Interestingly, MM.1S cells treated with TriC for 24 h also showed decreased mitochondrial ATP production rates and overall lower cellular respiration.

Overdevelopment of visceral adipose is positively correlated with the etiology of obesity‐associated pathologies including cardiovascular disease and insulin resistance. However, identification of genetic, molecular, and physiological factors regulating adipose development and function in response to nutritional stress is incomplete. Fibroblast Growth Factor 1 (FGF1) is a cytokine expressed and released by both adipocytes and endothelial cells under hypoxia, thermal, and oxidative stress. Expression of Fibroblast Growth Factor 1 (FGF1) in adipose is required for normal depot development and remodeling. Loss of FGF1 leads to deleterious changes in adipose morphology, metabolism, and insulin resistance. Conversely, diabetic and obese mice injected with recombinant FGF1 display improvements in insulin sensitivity and a reduction in adiposity. We report in this novel, in vivo study that transgenic mice expressing an endothelial‐specific FGF1 transgene (FGF1‐Tek) are resistant to high‐fat diet‐induced abdominal adipose accretion and are more glucose‐tolerant than wild‐type control animals. Metabolic chamber analyses indicate that suppression of the development of visceral adiposity and insulin resistance was not associated with alterations in appetite or resting metabolic rate in the FGF1‐Tek strain. Instead, FGF1‐Tek mice display increased locomotor activity that likely promotes the utilization of dietary fatty acids before they can accumulate in adipose and liver. This study provides insight into the impact that genetic differences dictating the production of FGF1 has on the risk for developing obesity‐related metabolic disease in response to nutritional stress. Mice overexpressing an FGF1 transgene (FGF1‐Tek) are resistant to high‐fat diet‐induced abdominal adipose accretion and are more glucose‐tolerant than FVB control animals. Metabolic chamber analyses indicate that suppression of the development of visceral adiposity and insulin resistance was not associated with alterations in appetite or resting metabolic rate in the FGF1‐Tek strain; instead, FGF1‐Tek mice display increased locomotor activity that likely promotes the utilization of dietary fatty acids before they can accumulate in adipose and liver. In addition, the visceral white adipose of FGF1‐Tek mice is marked by smaller adipocytes and larger areas of “beiging” in comparison to FVB Control animals. This study provides insight into the impact that genetic differences dictating the production of FGF1 has on the risk for developing obesity‐related metabolic disease in response to nutritional stress.

Obesity and calorie restriction each negatively affect skeletal health. Despite the negative effects of weight loss on the skeleton, obese patients are advised to lose weight via calorie restriction. Additionally, obesity and weight loss individually alter both whole-body and local metabolism. Little is known about bone quality and changes to the cortical metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would worsen bone quality in obese mice by shifting the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL6/J mice received 60% high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30% caloric restriction. Control animals received a 10% low-fat diet. Bodyweight and fat mass were increased by obesity and decreased with calorie restriction. Similarly, glucose and insulin tolerance were worsened with obesity but improved by weight loss. Compared to obesity, calorie restriction elicited more bone loss in both cortical and trabecular compartments. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. Our findings highlight the negative effects of obesity and subsequent caloric restriction on the skeleton. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models did not restore bone morphology or the cortical metabolome to control conditions.

MicroRNAs (miRNAs) are frequently encoded within polycistronic clusters thought to function as coherent regulatory units, yet whether individual cluster members act cooperatively or exert distinct physiological effects remains unclear. miR-27a and miR-27b are closely related miRNAs located within separate paralogous miR-23/27/24 clusters, but their in vivo relationship is unresolved. Using isoform-specific knockout models generated by precise CRISPR-based excision of individual miRNA hairpins, we defined how miR-27a and miR-27b regulate adipose thermogenesis and systemic metabolism. High-fat feeding increased miR-27a/b expression and suppressed thermogenic gene programs in subcutaneous white adipose tissue. In primary beige and brown adipocytes, loss of either isoform produced modest activation of thermogenic programs, whereas combined deletion caused additive increases in Ucp1 expression and mitochondrial DNA content. Ex vivo heat production was significantly elevated in double-knockout adipose explants relative to wild-type and single-knockout controls. In vivo, double-knockout mice exhibited increased energy expenditure and, under high-fat diet conditions, reduced adiposity with improved glucose homeostasis compared with wild-type and single-knockout mice. In contrast to metabolic dysfunction reported following whole-cluster deletion, selective miR-27 loss reveals a protective thermogenic program. These findings demonstrate that miRNA clusters need not act as coherent regulatory modules and identify miR-27a/b as a cooperative thermogenic checkpoint with therapeutic implications. * CRISPR isoform-specific knockouts isolate miR-27a/b contributions to metabolism. *Dual miR-27a/b loss drives cooperative thermogenic activation. *Double knockouts enhance energy expenditure and metabolic fitness in diet-induced obesity. *miR-27a/b deletion reveals that clustered miRNAs can exert non-coherent regulatory roles.