The splicing factor SF3B1 is involved in brown adipocyte thermogenic activation.

The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.

A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy.

FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning.

Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.

Circulating GDF15 concentrations in girls with low birth weight: effects of prolonged metformin treatment.

BACKGROUND: Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair <8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning. METHODS: Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up. RESULTS: Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat. CONCLUSION: Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term. IMPACT: Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.

Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation.

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.

Downregulation of peripheral lipopolysaccharide binding protein impacts on perigonadal adipose tissue only in female mice.

BACKGROUND AND AIMS: The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism. METHODS: The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice. RESULTS: Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males. CONCLUSION: LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.

The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity.

OBJECTIVES: To determine the role of armadillo repeat-containing X-linked protein 3 (ARMCX3) in the thermogenic plasticity of adipose tissue. METHODS: Adipose tissues were characterized in Armcx3-KO male mice. Armcx3 gene expression was analyzed in adipose tissue from mice exposed to thermogenic inducers (cold, ß3-adenergic stimulus) and in differentiating brown and beige cells in culture. Analyses encompassed circulating metabolite and hormonal profiling, tissue characterization, histology, gene expression patterns, and immunoblot assays. Armcx3 gene expression was assessed in subcutaneous adipose tissue from lean individuals and individuals with obesity and was correlated with expression of marker genes of adipose browning. The effects of adenoviral-mediated overexpression of ARMCX3 on differentiating brown adipocyte gene expression and respiratory activity were determined. RESULTS: Male mice lacking ARMCX3 showed significant induction of white adipose tissue browning. In humans, ARMCX3 expression in subcutaneous adipose tissue was inversely correlated with the expression of marker genes of thermogenic activity, including CIDEA, mitochondrial transcripts, and creatine kinase-B. Armcx3 expression in adipose tissues was repressed by thermogenic activation (cold or ß3-adrenergic stimulation) and was upregulated by obesity in mice and humans. Experimentally-induced increases in Armcx3 caused down-regulation of thermogenesis-related genes and reduced mitochondrial oxidative activity of adipocytes in culture, whereas siRNA-mediated Armcx3 knocking-down enhanced expression of thermogenesis-related genes. CONCLUSION: ARMCX3 is a novel player in the control of thermogenic adipose tissue plasticity that acts to repress acquisition of the browning phenotype and shows a direct association with indicators of obesity in mice and humans.

Bone Morphogenetic Protein-8B Levels at Birth and in the First Year of Life: Relation to Metabolic-Endocrine Variables and Brown Adipose Tissue Activity.

Objective: Bone morphogenetic protein-8B (BMP8B) is an adipokine produced by brown adipose tissue (BAT) contributing to thermoregulation and metabolic homeostasis in rodent models. In humans, BAT activity is particularly relevant in newborns and young infants. We assessed BMP8B levels and their relationship with BAT activity and endocrine-metabolic parameters in young infants to ascertain its potentiality as biomarker in early life. Materials and Methods: BMP8B concentrations were assessed longitudinally by ELISA in a cohort of 27 girls and 23 boys at birth, and at age 4 and 12 months, together with adiposity parameters (DXA), and circulating endocrine-metabolic variables. BAT activity was measured by infrared thermography. BMP8B gene expression (qRT-PCR) was determined in BAT, white fat, and liver samples from neonatal necropsies, and in placenta and cord blood. Results: BMP8B levels were high at birth, particularly in boys (P = 0.04 vs. girls), declined progressively, and remained well above those in healthy adults and pregnant women at age 1 year (P < 0.05 and P < 0.001, respectively). Neonatal BMP8B transcript levels were higher in BAT than in white fat, liver and cord blood. Circulating BMP8B levels during the first year of life marginally correlated with bone mineral density and gains in lean mass. Conclusion: BMP8B levels are high at birth and decline progressively over the first year of life remaining above adult levels. Although changes in BMP8B concentrations overall reflect those in BAT activity during development, BMP8B levels are unlikely to be useful to predict individual variations in endocrine-metabolic status and BAT activity in healthy young infants.

Adipose tissue aging partially accounts for fat alterations in HIV lipodystrophy.

Lipodystrophy is a major disturbance in people living with HIV-1 (PLWH). Several systemic alterations in PLWH are reminiscent of those that occur in ageing. It is unknown whether the lipodystrophy in PLWH is the consequence of accelerated ageing in adipose tissue. We compared systemic and adipose tissue disturbances in PLWH with those in healthy elderly individuals (~80 y old). We observed similarly enhanced expression of inflammation-related genes and decreased autophagy in adipose tissues from elderly individuals and PLWH. Indications of repressed adipogenesis and mitochondrial dysfunction were found specifically in PLWH, whereas reduced telomere length and signs of senesce were specific to elderly individuals. We conclude that ageing of adipose tissue accounts only partially for the alterations in adipose tissues of PLWH.

Specific adipose tissue Lbp gene knockdown prevents diet-induced body weight gain, impacting fat accretion-related gene and protein expression.

Lipopolysaccharide binding protein (Lbp) has been recently identified as a relevant component of innate immunity response associated to adiposity. Here, we aimed to investigate the impact of adipose tissue Lbp on weight gain and white adipose tissue (WAT) in male and female mice fed an obesogenic diet. Specific adipose tissue Lbp gene knockdown was achieved through lentiviral particles containing shRNA-Lbp injected through surgery intervention. In males, WAT Lbp mRNA levels increased in parallel to fat accretion, and specific WAT Lbp gene knockdown led to reduced body weight gain, decreased fat accretion-related gene and protein expression, and increased inguinal WAT basal lipase activity, in parallel to lowered plasma free fatty acids, leptin, triglycerides but higher glycerol levels, resulting in slightly improved insulin action in the insulin tolerance test. In both males and females, inguinal WAT Lbp gene knockdown resulted in increased Ucp1 and Ppargc1a mRNA and Ucp1 protein levels, confirming adipose Lbp as a WAT browning repressor. In perigonadal WAT, Lbp gene knockdown also resulted in increased Ucp1 mRNA levels, but only in female mice, in which it was 500-fold increased. These data suggest specific adipose tissue Lbp gene knockdown as a possible therapeutic approach in the prevention of obesity-associated fat accretion.

Posterior Cervical Brown Fat and CXCL14 Levels in the First Year of Life: Sex Differences and Association With Adiposity.

CONTEXT: Brown adipose tissue (BAT) is particularly abundant in neonates, but its association with measures of adiposity and metabolic health in early infancy is poorly delineated. Besides sustaining nonshivering thermogenesis, BAT secretes brown adipokines that act on systemic metabolism. The chemokine CXCL14 has been identified as a brown adipokine in experimental studies. OBJECTIVE: To determine the relationships among BAT activity, adiposity, and circulating CXCL14 levels in the first year of life in girls and boys. METHODS: Indices of fat accretion, circulating endocrine-metabolic parameters and serum CXCL14 levels were assessed longitudinally in a cohort of infants at birth and at 4 and 12 months. BAT activity was estimated using infrared thermography only at age 12 months.The main outcome measures were weight and length Z-scores, total and abdominal fat content (by dual X-ray absorptiometry), BAT activity at the posterior cervical and supraclavicular regions, serum levels of glucose, insulin, insulin-like growth factor-I, high-molecular-weight adiponectin, and CXCL14; CXCL14 transcript levels in neonatal BAT and liver. RESULTS: Posterior cervical BAT was more active in girls than in boys (P = .02). BAT activity was negatively associated with adiposity parameters only in girls. CXCL14 levels were higher in girls than in boys at age 12 months and correlated positively with the area of active posterior cervical BAT in girls. Neonatal BAT showed high CXCL14 gene expression levels. CONCLUSION: BAT activity and the levels of CXCL14-a potential surrogate of BAT activity-are sex specific in the first year of life. Posterior cervical BAT activity associates negatively with indices of adiposity only in girls.

The endocrine role of brown adipose tissue: An update on actors and actions.

In recent years, brown adipose tissue (BAT) has been recognized not only as a main site of non-shivering thermogenesis in mammals, but also as an endocrine organ. BAT secretes a myriad of regulatory factors. These so-called batokines exert local autocrine and paracrine effects, as well as endocrine actions targeting tissues and organs at a distance. The endocrine batokines include peptide factors, such as fibroblast growth factor-21 (FGF21), neuregulin-4 (NRG4), phospholipid transfer protein (PLTP), interleukin-6, adiponectin and myostatin, and also lipids (lipokines; e.g., 12,13-dihydroxy-9Z-octadecenoic acid [12,13-diHOME]) and miRNAs (e.g., miR-99b). The liver, heart, and skeletal muscle are the most commonly reported targets of batokines. In response to BAT thermogenic activation, batokines such as NRG4 and PLTP are released and act to reduce hepatic steatosis and improve insulin sensitivity. Stress-induced interleukin-6-mediated signaling from BAT to liver favors hepatic glucose production through enhanced gluconeogenesis. Batokines may act on liver to induce the secretion of regulatory hepatokines (e.g. FGF21 and bile acids in response to miR-99b and PLTP, respectively), thereby resulting in a systemic expansion of BAT-originating signals. Batokines also target extrahepatic tissues: FGF21 and 12,13-diHOME are cardioprotective, whereas BAT-secreted myostatin and 12,13-diHOME influence skeletal muscle development and performance. Further research is needed to ascertain in humans the role of batokines, which have been identified mostly in experimental models. The endocrine role of BAT may explain the association between active BAT and a healthy metabolism in the human system, which is characterized by small amounts of BAT and a likely moderate BAT-mediated energy expenditure.

Overexpression of CERKL Protects Retinal Pigment Epithelium Mitochondria from Oxidative Stress Effects.

The precise function of CERKL, a Retinitis Pigmentosa (RP) causative gene, is not yet fully understood. There is evidence that CERKL is involved in the regulation of autophagy, stress granules, and mitochondrial metabolism, and it is considered a gene that is resilient against oxidative stress in the retina. Mutations in most RP genes affect photoreceptors, but retinal pigment epithelium (RPE) cells may be also altered. Here, we aimed to analyze the effect of CERKL overexpression and depletion in vivo and in vitro, focusing on the state of the mitochondrial network under oxidative stress conditions. Our work indicates that the depletion of CERKL increases the vulnerability of RPE mitochondria, which show a shorter size and altered shape, particularly upon sodium arsenite treatment. CERKL-depleted cells have dysfunctional mitochondrial respiration particularly upon oxidative stress conditions. The overexpression of two human CERKL isoforms (558 aa and 419 aa), which display different protein domains, shows that a pool of CERKL localizes at mitochondria in RPE cells and that CERKL protects the mitochondrial network-both in size and shape-against oxidative stress. Our results support CERKL being a resilient gene that regulates the mitochondrial network in RPE as in retinal neurons and suggest that RPE cell alteration contributes to particular phenotypic traits in patients carrying CERKL mutations.

Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.

Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.

Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina.

The retina is a highly active metabolic organ that displays a particular vulnerability to genetic and environmental factors causing stress and homeostatic imbalance. Mitochondria constitute a bioenergetic hub that coordinates stress response and cellular homeostasis, therefore structural and functional regulation of the mitochondrial dynamic network is essential for the mammalian retina. CERKL (ceramide kinase like) is a retinal degeneration gene whose mutations cause Retinitis Pigmentosa in humans, a visual disorder characterized by photoreceptors neurodegeneration and progressive vision loss. CERKL produces multiple isoforms with a dynamic subcellular localization. Here we show that a pool of CERKL isoforms localizes at mitochondria in mouse retinal ganglion cells. The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism. Our results support CERKL as a regulator of autophagy and mitochondrial biology in the mammalian retina.

ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity.

ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.

Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health.

Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.

Adipose tissue knockdown of lysozyme reduces local inflammation and improves adipogenesis in high-fat diet-fed mice.

Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.