Obesity is associated with severe consequences for the renal system, including chronic kidney disease, kidney failure and increased mortality. Obesity has both direct and indirect effects on kidney health through several mechanisms, including activation of the renin-angiotensin system, mechanical compression, inflammation, fibrosis, increased filtration barrier permeability and renal nerve activity. The expansion of adipose tissue through hypertrophy and hyperplasia can induce haemodynamic changes that promote glomerular hyperfiltration to compensate for the greater metabolic demands of the increased body weight. Adipose expansion is also associated with the release of adipokines and pro-inflammatory cytokines, hyperinsulinaemia and insulin resistance, which exert direct and indirect effects on kidney function via various mechanisms. Increased uptake of fatty acids by the kidney leads to alterations in lipid metabolism and lipotoxicity, also contributing to the pro-inflammatory and pro-fibrotic environment. The role of the adipose tissue-brain-kidney axis in the obesity-associated decline in renal function is sustained by studies showing that stimulation of adipose tissue sensory neurons by locally released factors increases renal sympathetic nerve activity. Conversely, pre-existent kidney disease can contribute to adipose dysfunction through the accumulation of uraemic toxins and hormonal changes. These findings highlight the importance of crosstalk between adipose tissue and the kidneys and provide insights into the mechanisms underlying the associations between obesity and kidney disease.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.

The escalating incidence of obesity, diabetes, and insulin resistance has become a significant global health concern. In this study, we have developed a self-nanoemulsifying delivery system (SNEDS) of formononetin-vitamin E conjugate (VESylated-FMN) for improving its oral bioavailability and improving insulin sensitivity and glycemic control. The developed SNEDS were characterized using dynamic light scattering and transmission electron microscopy. Thereafter, the loading capacity, in vitro release, thermodynamic, and gastrointestinal stability of the developed formulation were evaluated. The safety and oral bioavailability of VESylated-FMN-SNEDS were assessed in Sprague-Dawley rats, whereas insulin-sensitizing potency was assessed in high-fat diet-induced type 2 diabetic mice. The VESylated-FMN-SNEDS quickly emulsified on dilution (droplet size ∼79.17 nm) and showed remarkable thermodynamic and gastrointestinal stability. The developed formulation demonstrated enhanced oral bioavailability (∼1.3-fold higher AUC0-t) of VESylated-FMN without liver and kidney injury. Consequently, VESylated-FMN-SNEDS significantly improves insulin sensitivity and glycemic control in HFD-fed mice compared to VESylated-FMN by upregulating the transcript level of insulin-sensitizing genes. Therefore, the SNEDS formulation could be an effective strategy to augment the oral bioavailability and insulin-sensitizing potency of VESylated-FMN.

Obesity may be more prevalent among populations who are of low socioeconomic status, have limited access to nutrient-dense foods, or both. One such population is justice-involved youth. This series of translational experiments builds on previous research on food reinforcement and behavioral demand by (a) assaying demand for snack foods among justice-involved adolescents and (b) evaluating the effect of a nutrition intervention on justice-involved adolescents' demand for healthier alternatives. In Experiment 1, participants completed preference assessments for high- and low-energy-density snack foods and corresponding commodity purchasing tasks. The results indicated significant differences in demand based on energy density and preference. In Experiment 2, justice-involved adolescents received a nutrition intervention. Following intervention, participants repeated preference assessments and commodity purchasing tasks. The researchers used mixed-effects modeling to evaluate the effect of (a) the intervention, (b) participant age, and (c) the amount of intervention received on pre-post differences in demand for healthier alternatives. Results and implications are discussed along with future directions for improving conditions of confinement for justice-involved adolescents.

Brown adipose tissue (BAT) represents an evolutionary innovation enabling placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are surrounded by a dense network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure stimulates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we identify Slit guidance ligand 3 (Slit3) as a new niche factor that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We show that adipocyte progenitors secrete Slit3 which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which activate distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. Moreover, we introduce bone morphogenetic protein-1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this study underscores the essential role of Slit3-mediated neurovascular network expansion in enabling cold-induced BAT adaptation. The co-regulation of neurovascular expansion by Slit3 fragments provides a bifurcated yet harmonized approach to ensure a synchronized response of BAT to environmental challenges. This study presents the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling.

To show that electroacupuncture stimulation (ES) remodels sympathetic innervation in brown adipose tissue (BAT) via the bone morphogenic protein 8B (BMP8B)-neuregulin 4 (NRG4)-ErbB4 axis, with somatotopic dependence.

We established a high-fat diet (HFD) model with C57BL/6J mice to measure the thermogenesis and metabolism of BAT. In addition, the sympathetic nerve activity (SNA) was measured with the electrophysiological technique, and the immunostaining of c-Fos was used to detect the central nervous system sources of sympathetic outflows. Finally, the key role of the BMP8B-NRG4-ErbB4 axis was verified by peripheral specific antagonism of ErbB4.

ES at the forelimb and abdomen regions significantly up-regulate SNA, whereas ES at the hindlimb region has a limited regulatory effect on SNA but still partially restores HFD-induced BAT dysfunction. Mechanistically, ES at the forelimb and abdomen regions driving catecholaminergic signals in brown adipocytes depends on neural activities projected from the ventromedial nucleus of the hypothalamus (VMH) to the spinal cord intermediolateral column (IML). Notably, the peripheral suppression of ErbB4 in BAT inhibits the thermogenesis and metabolic function of BAT, as well as significantly hindering the SNA activation and metabolic benefits induced by ES.

These results suggest that ES appears to be an effective approach for remodeling sympathetic innervation in BAT, which is closely related to neuronal activity in the VMH and the NRG4-ErbB4 signaling pathway.

Background: Enhancing white adipose tissue (WAT) browning combats obesity. The RIIβ subunit of cAMP-dependent protein kinase (PKA) is primarily expressed in the brain and adipose tissue. Deletion of the hypothalamic RIIβ gene centrally induces WAT browning, yet the peripheral mechanisms mediating this process remain unexplored. Methods: This study investigates the mechanisms underlying WAT browning in RIIβ-KO mice. Genetic approaches such as β3-adrenergic receptors (β3ARs) deletion and sympathetic denervation of WAT were utilized. Genome-wide transcriptomic sequencing and bioinformatic analysis were employed to identify potential mediators of WAT browning. siRNA assays were employed to knock down mTOR and lipin1 in vitro, while AAV-shRNAs were used for the same purpose in vivo. Results: We found that WAT browning substantially contributes to the lean and obesity-resistant phenotypes of RIIβ-KO mice. The WAT browning can be dampened by β3ARs deletion or WAT sympathetic denervation. We identified that adipocytic mTOR and lipin1 may act as mediators of the WAT browning. Inhibition of mTOR or lipin1 abrogates WAT browning and hinders the lean phenotype of RIIβ-KO mice. In human subcutaneous white adipocytes and mouse white adipocytes, β3AR stimulation can activate mTOR and causes lipin1 nuclear translocation; knockdown of mTOR and Lipin1 mitigates WAT browning-associated gene expression, impedes mitochondrial activity. Moreover, mTOR knockdown reduces lipin1 level and nuclear translocation, indicating that lipin1 may act downstream of mTOR. Additionally, in vivo knockdown of mTOR and Lipin1 diminished WAT browning and increased adiposity. Conclusions: The β3AR-activated mTOR-lipin1 axis mediates WAT browning, offering new insights into the molecular basis of PKA-regulated WAT browning. These findings provide potential adipose target candidates for the development of drugs to treat obesity.

Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.

This study aimed to investigate the therapeutic potential of Citrullus mucosospermus extract (CME) in counteracting adipogenesis and its associated metabolic disturbances in murine models. In vitro experiments utilizing 3T3-L1 preadipocytes revealed that CME potently inhibited adipocyte differentiation, as evidenced by a dose-dependent reduction in lipid droplet formation. Remarkably, CME also attenuated glucose uptake and intracellular triglyceride accumulation in fully differentiated adipocytes, suggesting its ability to modulate metabolic pathways in mature adipose cells. Translating these findings to an in vivo setting, we evaluated the effects of CME in C57BL/6N mice fed a high-fat diet (HFD) for 10 weeks. CME administration, concomitantly with the HFD, resulted in a significant attenuation of body weight gain compared to the HFD control group. Furthermore, CME treatment led to substantial reductions in liver weight, total fat mass, and deposits of visceral and retroperitoneal adipose tissue, underscoring its targeted impact on adipose expansion. Histological analyses revealed the remarkable effects of CME on hepatic steatosis. While the HFD group exhibited severe lipid accumulation within liver lobules, CME dose-dependently mitigated this pathology, with the highest dose virtually abolishing hepatic fat deposition. An examination of adipose tissue revealed a progressive reduction in adipocyte hypertrophy upon CME treatment, culminating in a near-normalization of adipocyte morphology at the highest dose. Notably, CME exhibited potent anti-inflammatory properties, significantly attenuating the upregulation of pro-inflammatory cytokines' mRNA levels (TNF-α, IL-1β and IL-6) in the livers of HFD-fed mice. This suggests a potential mechanism through which CME may exert protective effects against inflammation associated with obesity and fatty liver disease.

Adipose tissue innervation is critical for regulating metabolic and energy homeostasis. While the sympathetic efferent innervation of fat is well characterized, the role of sensory or afferent innervation remains less explored. This article reviews previous work on adipose innervation and recent advances in the study of sensory innervation of adipose tissues. We discuss key open questions, including the physiological implications of adipose afferents in homeostasis as well as potential cross talk with sympathetic neurons, the immune system, and hormonal pathways. We also outline the general technical challenges of studying dorsal root ganglia innervating fat, along with emerging technologies that may overcome these barriers. Finally, we highlight areas for further research to deepen our understanding of the afferent function of adipose innervation.

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

In humans, glucocorticoids (GCs) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GCs often lead to side effects, including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared with control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of hypoxia-inducible factor 1α (HIF-1α) and proangiogenic vascular endothelial growth factor A (VEGFA) expression in GR-deficient adipocytes of AdipoGR-KO mice compared with control mice, together with an increased adipose vascular network, as assessed by three-dimensional imaging. GR activation reduced HIF-1α recruitment to the Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and posttranslational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from patients with Cushing syndrome, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the downregulation of the major angiogenic effector VEGFA and inhibition of vascular network development.

Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies.

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.

The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.

Sympathetic innervation of white adipose tissue (WAT) plays a key role in the regulation of lipid metabolism. Sympathetic activation promotes release of norepinephrine (NE), which binds to adrenergic receptors on adipocytes, promoting adipocyte lipolysis and enhanced oxidative metabolism. However, the mechanism by which sympathetic nerves regulate lipid metabolism in pig adipose tissue remains unclear. We used NE to simulate the process of sympathetic driving in pig adipocytes. RNA sequencing (RNA-seq) was used to determine the gene expression profile of pig adipocytes responding to NE stimulation. Our data suggests that the lipolytic signaling pathway is activated in pig adipocytes upon acute stimulation of NE, resulting in enhanced lipid metabolism and lipolysis, consistent with the phenomena found in humans and mice. Specifically, differentially expressed protein coding genes (PCGs) (SIRT4, SLC27A1) are mainly associated with functions that inhibit fatty acid oxidation and promote lipid synthesis. Similarly, we investigated the changes in regulatory transcripts such as long non-coding RNAs (lncRNAs) and transcripts of uncertain coding potential (TUCP) in response to NE and found that differentially expressed lncRNAs (lncG47338, lncG30660, lncG29516, lncG3790) and TUCP (TUCP_G38001) were co-expressed with target genes related to the promotion of fatty acid β-oxidation, lipolysis and oxidative metabolism, thus acting as regulators. These results indicate a broad suite of gene expression alterations in response to NE stimulation and promote the understanding of the molecular mechanisms by which NE regulates lipid metabolism in pigs.

To evaluate the impact of jatobá-do-cerrado flour on nutritional, inflammatory, and oxidative stress markers, an study was conducted using male Wistar rats. These animals were allocated into four groups: a standard diet (Control), a high-fat diet (HFD), a diet with jatobá-do-cerrado flour (JCF), and a combination of high-fat diet and jatobá-do-cerrado flour (HFD + JCF). Comprehensive evaluations included food intake, cytokine concentrations, and redox status indicators. HFD group exhibited increased caloric intake and fat mass, elevated circulating IL-6, and heightened lipid peroxidation markers. This group also showed increased hypothalamic concentrations of IL-6, TNFα, and lipid peroxidation. In contrast, the HFD + JCF group showed reduced caloric intake, fat mass, and improvements in redox balance and inflammatory markers both in the blood and hypothalamus. SUMMARY: In the current study, we evaluated the potential of Jatobá-do-cerrado flour in mitigating the effects of a high-fat diet in adult Wistar rats. The addition of fat to the animals' diet for 63 days induced obesity, dyslipidemia, as well as an increase in inflammatory and lipid peroxidation markers, both in the blood and hypothalamus. Conversely, supplementation with Jatobá-do-Cerrado flour showed anti-obesogenic effects and these may be associated with the reduction of inflammation and oxidative stress. Therefore, supplementation with this flour has the potential to be a functional food for the treatment or prevention of obesity.

We conducted a large-scale investigation of the systemic and adipose tissue-specific alterations in a clinical population of burn patients to identify factors that may influence hypermetabolism.

Previous research has identified chronic disturbances in adipose tissue inflammation, lipolysis, and browning, which may drive the perpetuation of hypermetabolism following the severe adrenergic stress of a burn injury. Given that adipose tissue is thought to be a central node in the regulation of systemic metabolism, we believe that systematically delineating the pathologic role of adipose tissue postburn, will lead to the identification of novel interventions to mitigate morbidity and mortality from severe burns.

This was a single-institution cohort study, which obtained plasma and subcutaneous adipose tissue samples from severely burn adult patients over various time points during acute hospitalization. Whole-body clinical, metabolic, and inflammatory mediators were assessed in plasma, while genetic analyses through RT-qPCR and single-nuclei RNA sequencing were conducted in adipose tissue.

Systemic inflammation and adrenergic stress increase IL-6 signaling, lipolysis, browning, and adipokine dysfunction in the adipose tissue of adult burn patients, which may further propagate the long-term hypermetabolic response. Moreover, using single-nuclei RNA sequencing, we provide the first comprehensive characterization of alterations in the adipose tissue microenvironment occurring at acute and chronic stages postburn.

We provide novel insight toward the effect of burns on adipokine release, inflammatory signaling pathways, and adipose heterogeneity over the trajectory of acute and chronic stages.

Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of cardiovascular health and disease, mediated in part by the endocrine and paracrine secretion of several bioactive products, such as adipokines. Adipose vasculature has an instrumental role in the modulation of adipose tissue expansion, homeostasis and metabolism. The role of the adipose vasculature has been extensively explored in the context of obesity, which is recognized as a global health problem. Obesity-induced accumulation of fat, in combination with vascular rarefaction, promotes adipocyte dysfunction and induces oxidative stress, hypoxia and inflammation. It is now recognized that obesity-associated endothelial dysfunction often precedes the development of cardiovascular diseases. Investigations have revealed heterogeneity within the vascular niche and dynamic reciprocity between vascular and adipose cells, which can become dysregulated in obesity. Here we provide a comprehensive overview of the evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.

Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPβ for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.

White, beige, and brown adipose tissues play a crucial role in maintaining energy homeostasis. Due to the heterogeneous and diffuse nature of fat pads, this balance requires a fine and coordinated control of many actors and therefore permanent dialogues between these tissues and the central nervous system. For about two decades, many studies have been devoted to describe the neuro-anatomical and functional complexity involved to ensure this dialogue. Thus, if it is now clearly demonstrated that there is an efferent sympathetic innervation of different fat depots controlling plasticity as well as metabolic functions of the fat pad, the crucial role of sensory innervation capable of detecting local signals informing the central nervous system of the metabolic state of the relevant pads is much more recent. The purpose of this review is to provide the current state of knowledge on this subject.

Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported stress-induced alterations in haematopoiesis that result in monocytosis, neutrophilia, lymphocytopenia and, consequently, in the upregulation of pro-inflammatory processes in immunologically relevant peripheral tissues. There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms as well as to common co-morbidities of psychiatric disorders such as metabolic syndrome and immunosuppression. Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function. We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver. Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation or intracerebroventricular administration of peptide hormones to control somatic immune responses. Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and comorbid pathophysiology.

Homeostatic regulation of adipose tissue is critical for the maintenance of energy balance and whole-body metabolism. The peripheral nervous system provides bidirectional neural communication between the brain and adipose tissue, thereby providing homeostatic control. Most research on adipose innervation and nerve functions has been limited to the sympathetic nerves and their neurotransmitter norepinephrine. In recent years, more work has focused on adipose sensory nerves, but the contributions of subsets of sensory nerves to metabolism and the specific roles contributed by sensory neuropeptides are still understudied. Advances in imaging of adipose innervation and newer tissue denervation techniques have confirmed that sensory nerves contribute to the regulation of adipose functions, including lipolysis and browning. Here, we summarize the historical and latest findings on the regulation, function and plasticity of adipose tissue sensory nerves that contribute to metabolically important processes such as lipolysis, vascular control and sympathetic axis cross-talk.

Efficient communication between the brain and peripheral organs is indispensable for regulating physiological function and maintaining energy homeostasis. The peripheral nervous system (PNS) in vertebrates, consisting of the autonomic and somatic nervous systems, bridges the peripheral organs and the central nervous system (CNS). Metabolic signals are processed by both vagal sensory nerves and somatosensory nerves. The CNS receives sensory inputs via ascending nerves, serves as the coordination and integration center, and subsequently controls internal organs and glands via descending nerves. The autonomic nervous system consists of sympathetic and parasympathetic branches that project peripheral nerves into various anatomical locations to regulate the energy balance. Sympathetic and parasympathetic nerves typically control the reflexive and involuntary functions in organs. In this review article, we outline the innervation of adipose tissue, gut, pancreas, and liver, to illustrate the neurobiological basis of central-peripheral interactions. We emphasize the importance of understanding the functional atlas of neural control of energy metabolism, and more importantly, provide potential avenues for further research in this area.

Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the composition and function of immune cells. Such synergistic adaptation requires extensive crosstalk between individual cells in the tissue to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we apply the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We construct an integrative network of the ligand-receptor interactome in BAT and identify the major signaling inputs and outputs of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we show that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated and non-myelinated Schwann cells, and immune cells. These interactions are predicted to regulate the remodeling of the extracellular matrix, the inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures provides a new understanding of the mechanisms underlying BAT thermogenesis. The resources presented in this study offer a valuable platform for future investigations of BAT development and thermogenesis.

In previous studies, adipocytes were found to play an important role in regulating whole-body nutrition and energy balance, and are also important in energy metabolism, hormone secretion, and immune regulation. Different adipocytes have different contributions to the body, with white adipocytes primarily storing energy and brown adipocytes producing heat. Recently discovered beige adipocytes, which have characteristics in between white and brown adipocytes, also have the potential to produce heat. Adipocytes interact with other cells in the microenvironment to promote blood vessel growth and immune and neural network interactions. Adipose tissue plays an important role in obesity, metabolic syndrome, and type 2 diabetes. Dysfunction in adipose tissue endocrine and immune regulation can cause and promote the occurrence and development of related diseases. Adipose tissue can also secrete multiple cytokines, which can interact with organs; however, previous studies have not comprehensively summarized the interaction between adipose tissue and other organs. This article reviews the effect of multi-organ crosstalk on the physiology and pathology of adipose tissue, including interactions between the central nervous system, heart, liver, skeletal muscle, and intestines, as well as the mechanisms of adipose tissue in the development of various diseases and its role in disease treatment. It emphasizes the importance of a deeper understanding of these mechanisms for the prevention and treatment of related diseases. Determining these mechanisms has enormous potential for identifying new targets for treating diabetes, metabolic disorders, and cardiovascular diseases.

Arjunolic acid (AA) is a potent phytochemical with multiple therapeutics effects. In this study, AA is evaluated on type 2 diabetic (T2DM) rats to understand the mechanism of β-cell linkage with Toll-like receptor 4 (TLR-4) and canonical Wnt signaling. However, its role in modulating TLR-4 and canonical Wnt/β-catenin crosstalk on insulin signaling remains unclear during T2DM. Aim The current study is aimed to examine the potential role of AA on insulin signaling and TLR-4-Wnt crosstalk in the pancreas of type 2 diabetic rats.

Multiple methods were used to determine molecular cognizance of AA in T2DM rats, when treated with different dosage levels. Histopathological and histomorphometry analysis was conducted using masson trichrome and H&E stains. While, protein and mRNA expressions of TLR-4/Wnt and insulin signaling were assessed using automated Western blotting (jess), immunohistochemistry, and RT-PCR.

Histopathological findings revealed that AA had reversed back the T2DM-induced apoptosis and necrosis caused to rats pancreas. Molecular findings exhibited prominent effects of AA in downregulating the elevated level of TLR-4, MyD88, NF-κB, p-JNK, and Wnt/β-catenin by blocking TLR-4/MyD88 and canonical Wnt signaling in diabetic pancreas, while IRS-1, PI3K, and pAkt were all upregulated by altering the NF-κB and β-catenin crosstalk during T2DM.

Overall results, indicate that AA has potential to develop as an effective therapeutic in the treatment of T2DM associated meta-inflammation. However, future preclinical research at multiple dose level in a long-term chronic T2DM disease model is warranted to understand its clinical relevance in cardiometabolic disease.

The thermogenic brown and beige adipocytes consume fatty acids and generate heat to maintain core body temperature in the face of cold challenges. Since their validated presence in humans, the activation of thermogenic fat has been an attractive target for treating obesity and related metabolic diseases. Here, we reported that the opioid growth factor receptor (Ogfr) was highly expressed in adipocytes and promoted thermogenesis. The mice with genetic deletion of Ogfr in adipocytes displayed an impaired capacity to counter environmental cold challenges. Meanwhile, Ogfr ablation in adipocytes led to reduced fatty acid oxidation, enhanced lipid accumulation, impaired glucose tolerance, and exacerbated tissue inflammation under chronic high-fat diet (HFD)-fed conditions. At the cellular level, OGFr enhanced the production of mitochondrial trifunctional protein subunit α (MTPα) and also interacted with MTPα, thus promoting fatty acid oxidation. Together, our study demonstrated the important role of OGFr in fatty acid metabolism and adipose thermogenesis.

The increasing prevalence of obesity and type 2 diabetes has led to a greater interest in adipose tissue physiology. Adipose tissue is now understood as an organ with endocrine and thermogenic capacities in addition to its role in fat storage. It plays a critical role in systemic metabolism and energy regulation, and its activity is tightly regulated by the nervous system. Fat is now recognized to receive sympathetic innervation, which transmits information from the brain, as well as sensory innervation, which sends information into the brain. The role of sympathetic innervation in adipose tissue has been extensively studied. However, the extent and the functional significance of sensory innervation have long been unclear. Recent studies have started to reveal that sensory neurons robustly innervate adipose tissue and play an important role in regulating fat activity. This brief review will discuss both historical evidence and recent advances, as well as important remaining questions about the sensory innervation of adipose tissue.

Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA.

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

The rising prevalence of type 2 diabetes mellitus (T2DM) and accompanying insulin resistance is alarming globally. Natural and synthetic agonists of PPARγ are potentially attractive candidates for diabetics and are known to efficiently reverse adipose and hepatic insulin resistance, but related side effects and escalating costs are the causes of concern. Therefore, targeting PPARγ with natural ligands is advantageous and promising approach for the better management of T2DM. The present research aimed to assess the antidiabetic potential of phenolics Phloretin (PTN) and Phlorizin (PZN) type 2 diabetic mice.

In silico docking was performed to check the effect of PTN and PZN on PPARγ S273-Cdk5 interactions. The docking results were further validated in preclinical settings by utilizing a mice model of high fat diet-induced T2DM.

Computational docking and further MD-simulation data revealed that PTN and PZN inhibited the activation of Cdk5, thereby blocking the phosphorylation of PPARγ. Our in vivo results further demonstrated that PTN and PZN administration significantly improved the secretory functions of adipocytes by increasing adiponectin and reducing inflammatory cytokine levels, which ultimately reduced the hyperglycaemic index. Additionally, combined treatment of PTN and PZN decreased in vivo adipocyte expansion and increased Glut4 expression in adipose tissues. Furthermore, PTN and PZN treatment reduced hepatic insulin resistance by modulating lipid metabolism and inflammatory markers.

In summary, our findings strongly imply that PTN and PZN are candidates as nutraceuticals in the management of comorbidities related to diabetes and its complications.

Obesity is linked to metabolic, hormonal and biochemical alterations, and is also a risk factor for behavioral disorders. Evidence suggests that these disorders may be related to the consumption of hypercaloric diets, fat mass accumulation and changes in inflammation and redox status. Although much is known about the chronic effects of hypercaloric diets on mental health, few studies have evaluated the consequences of short-term exposure of these diets on behavior. The aim of this study was to evaluate nutritional, behavioral (anxiety-like), inflammatory and redox status parameters in adult male Wistar rats exposed to short-term cafeteria diet. Adult Wistar male rats (90 days-old; n = 12/group) received, during 14 days, the diets: Control- standard diet; Simple Cafeteria Diet (SCD)- homogeneous cafeteria diet. Varied Cafeteria Diet (VCD)- cafeteria diet with rotation and variation. Nutritional analyzes and tests for anxiety-like behaviors were performed, in addition to inflammatory and redox status measurements in blood and amygdala. The SCD group showed higher fat energy intake, while the VCD group consumed more energy from carbohydrates. SCD and VCD showed higher fat mass accumulation, in addition to higher levels of TNFα, INFγ, TBARS and FRAP in the blood. Also, SCD and VCD groups reported high levels of TNFα in the amygdala. Regarding behavioral evaluations, SCD and VCD groups showed anxiogenesis in the elevated plus maze, light-dark box, and open field tests. Therefore, the two cafeteria diets induced obesity and systemic inflammation, which in turn, resulted in an increase in amygdala TNFα levels and anxiety-like behaviors in Wistar rats.

The RIIβ subunit of  cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIβ-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIβ reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIβ-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIβ-KO mice exhibit a robust WAT browning. RIIβ reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single-cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIβ-KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIβ-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIβ-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Accumulating evidence indicates that interoception maintains proper physiological status and orchestrates metabolic homeostasis by regulating feeding behaviors, glucose balance, and lipid metabolism. Continuous skeletal remodeling consumes a tremendous amount of energy to provide skeletal scaffolding, support muscle movement, store vital minerals, and maintain a niche for hematopoiesis, which are processes that also contribute to overall metabolic balance. Although skeletal innervation has been described for centuries, recent work has shown that skeletal metabolism is tightly regulated by the nervous system and that skeletal interoception regulates bone homeostasis. Here, we provide a general discussion of interoception and its effects on the skeleton and whole-body metabolism. We also discuss skeletal interoception-mediated regulation in the context of pathological conditions and skeletal pain as well as future challenges to our understanding of these process and how they can be leveraged for more effective therapy.

The white adipose tissues (WAT) are located in distinct depots throughout the body. They serve as an energy reserve, providing fatty acids for other tissues via lipolysis when needed, and function as an endocrine organ to regulate systemic metabolism. Their activities are coordinated through intercellular communications among adipocytes and other cell types such as residential and infiltrating immune cells, which are collectively under neuronal control. The adipocytes and immune subtypes including macrophages/monocytes, eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2s), T and B cells, dendritic cells (DCs), and natural killer (NK) cells display cellular and functional diversity in response to the energy states and contribute to metabolic homeostasis and pathological conditions. Accumulating evidence reveals that neuronal innervations control lipid deposition and mobilization via regulating lipolysis, adipocyte size, and cellularity. Vice versa, the neuronal innervations and activity are influenced by cellular factors in the WAT. Though the literature describing adipose tissue cells is too extensive to cover in detail, we strive to highlight a selected list of neuronal and immune components in this review. The cell-to-cell communications and the perspective of neuroimmune regulation are emphasized to enlighten the potential therapeutic opportunities for treating metabolic disorders.