Seipin is a key regulator of lipid metabolism, the deficiency of which leads to severe lipodystrophy. Hypothalamus is the pivotal center of brain that modulates appetite and energy homeostasis, where Seipin is abundantly expressed. Whether and how Seipin deficiency leads to systemic metabolic disorders via hypothalamus-involved energy metabolism dysregulation remains to be elucidated. In the present study, we demonstrated that Seipin-deficiency induced hypothalamic inflammation, reduction of anorexigenic pro-opiomelanocortin (POMC), and elevation of orexigenic agonist-related peptide (AgRP). Importantly, administration of rosiglitazone, a thiazolidinedione antidiabetic agent, rescued POMC and AgRP expression, suppressed hypothalamic inflammation, and restored energy homeostasis in Seipin knockout mice. Our findings offer crucial insights into the mechanism of Seipin deficiency-associated energy imbalance and indicates that rosiglitazone could serve as potential intervening agent towards metabolic disorders linked to Seipin.

BACKGROUND: Research on the imbalance of proopiomelanocortin (POMC)/agouti-related protein (AgRP) neurons in the hypothalamus holds potential insights into the pathophysiology of diabetes. Jinkui Shenqi pills (JSP), a prevalent traditional Chinese medicine, regulate hypothalamic function and treat diabetes.
OBJECTIVE: To investigate the hypoglycemic effect of JSP and explore the probable mechanism in treating diabetes.
METHODS: A type 2 diabetes mouse model was used to investigate the pharmacodynamics of JSP. The glucose-lowering efficacy of JSP was assessed through various metrics including body weight, food consumption, fasting blood glucose (FBG), serum insulin levels, and an oral glucose tolerance test (OGTT). To elucidate the modulatory effects of JSP on hypothalamic mechanisms, we quantified the expression and activity of POMC and AgRP and assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (AKT)/forkhead box O1 (FOXO1) pathway in diabetic mice via western blotting and immunohistochemistry. Additionally, primary hypothalamic neurons were exposed to high glucose and palmitic acid levels to induce insulin resistance, and the influence of JSP on POMC/AgRP protein expression and activation was evaluated by PI3K protein inhibition using western blotting and immunofluorescence.
RESULTS: Medium- and high-dose JSP treatment effectively inhibited appetite, resulting in a steady declining trend in body weight, FBG, and OGTT results in diabetic mice (p < 0.05). These JSP groups also had significantly increased insulin levels (p < 0.05). Importantly, the medium-dose group exhibited notable protection of hypothalamic neuronal and synaptic structures, leading to augmentation of dendritic length and branching (p < 0.05). Furthermore, low-, medium-, and high-dose JSP groups exhibited increased phosphorylated (p) INSR, PI3K, pPI3K, AKT, and pAKT expression, as well as decreased FOXO1 and increased pFOXO1 expression, indicating improved hypothalamic insulin resistance in diabetic mice (p < 0.05). Treatment with 10% JSP-enriched serum produced a marked elevation of both expression and activation of POMC (p < 0.05), with a concurrent reduction in AgRP expression and activation within primary hypothalamic neurons (p < 0.05). Intriguingly, these effects could be attributed to the regulatory dynamics of PI3K activity.
CONCLUSIONS: Our findings suggest that JSP can ameliorate diabetes by regulating POMC/AgRP expression and activity. The insulin-mediated PI3K/AKT/FOXO1 pathway plays an important regulatory role in this intricate process.

OBJECTIVE: Metabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been an important clinical therapeutic measure in septic patients; however, simple EN has not demonstrated good performance. This study aimed to investigate the effects of different concentrations of octanoic acid (OA)-rich EN on hypercatabolism in endotoxemic rats and test whether OA-rich EN could attenuate hypercatabolism through the acylated ghrelin-proopiomelanocortin (POMC) pathway.
METHODS: Rats were randomly divided into six groups: sham, lipopolysaccharide (LPS), LPS + EN and LPS + EN + OA (0.25, 0.5, and 1 g/kg, respectively) groups to investigate the effects of different concentrations of OA-rich EN on hypercatabolism in endotoxemic rats. The rats were then randomly divided into four groups: sham, LPS, LPS + OA, and LPS + OA + Go-CoA-Tat, to test whether OA-rich EN attenuated hypercatabolism through the acylated ghrelin-POMC pathway. Rats received nutrition support via a gastric tube for 3 d (100 kcal/kg daily). Insulin resistance, muscle protein synthesis and atrophy, inflammatory cytokines, ghrelin in circulation and hypothalamus, ghrelin O-acyltransferase (GOAT), and the adenosine 5\'-monophosphate-activated protein kinase (AMPK)-autophagy-POMC pathway were measured.
RESULTS: Compared with simple EN, OA-rich EN promoted the acylation of ghrelin in a dose-dependent manner and attenuated POMC-mediated hypercatabolism in endotoxemic rats. Inhibition of GOAT activity decreased the level of acylated ghrelin and aggravated POMC-mediated hypercatabolism conferred by OA-rich EN.
CONCLUSIONS: OA-rich EN could increase the level of acylated ghrelin and attenuate hypercatabolism through the acylated ghrelin-POMC pathway compared with simple EN in endotoxemic rats.

UNASSIGNED: Insulin resistance (IR) is one of the common pathological manifestations of metabolic-related diseases, and the prevalence of relevant diseases is high. Acupuncture is beneficial to IR patients, but the central mechanism underlying this treatment remains unclear. This study provides mechanistic insights into how electroacupuncture (EA) improves IR through the response of Pro-opiomelanocortin (POMC) neurons to adiponectin (Adipo).
UNASSIGNED: Glucose tolerance tests (GTT), Insulin tolerance tests (ITT) and fasting blood glucose (FBG) were detected by glucometer. Serum insulin, Adipo and skeletal muscle adiponectin receptor 1 (AdipoR1) protein levels were examined by ELISA. Homeostasis model assessment estimated insulin resistance (HOMA-IR) was calculated using the following formula: HOMA-IR = fasting insulin (FINS) (mU/L) × FBG (mmol/L)/22.5. The expression levels of AdipoR1 and Adipo mRNA in skeletal muscle were detected by real-time PCR quantification. The co-marking of c-Fos/AdipoR1 and POMC neurons were investigated using immunofluorescence. Spontaneous excitatory postsynaptic currents (sEPSCs) of POMC neurons and the response of POMC neurons to Adipo were detected via electrophysiology.
UNASSIGNED: EA significantly ameliorated HFD-induced impairment of GTT, ITT, FBG, and HOMA-IR which was correlated with recovery of the expression level of AdipoR1 and Adipo in skeletal muscle. The improved response of POMC neurons to Adipo in the hypothalamus may be a key factor in correcting abnormal glucose tolerance and improving IR.
UNASSIGNED: This study demonstrates that EA can ameliorate HFD-induced impaired glucose tolerance through improved response of POMC neurons to Adipo in the hypothalamus, providing insight into the central mechanism of improving IR through EA.

The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.

BACKGROUND: Dietary astaxanthin (AST) exhibits the ability to resist lipid accumulation and stimulate hepatic autophagy. Natural AST predominantly exists in stable esterified forms. More importantly, in our previous study, docosahexaenoic acid-acylated AST monoester (AST-DHA) possessed better stability, bioavailability, and neuroprotective ability than AST in free and diester form. However, the AST-DHA mechanisms of action in regulating the obese phenotype and autophagy of the central nervous system remain unclear.
RESULTS: High-fat diet (HFD)-fed C57BL/6J mice were orally administered AST-DHA (50 mg/kg body weight/d) for 3 days or 8 weeks. AST-DHA supplementation alleviated HFD-induced abnormal body weight gain, significantly enhanced autophagy with an increased microtubule-associated protein light chain 3 II/I (LC3II/I) ratio, and reduced the accumulation of p62/sequestosome 1 (SQSTM1) in the hypothalamus rather than in the hippocampus. Mechanistically, AST-DHA effectively promoted autophagy and autophagosome formation, and most notably rescued the HFD-impaired autophagosome-lysosome fusion (indicated by the colocalization of LC3 and LAMP1) by regulating mTOR- and AMPK-induced phosphorylation of ULK1. Consequently, AST-DHA enhanced hypothalamic autophagy, leading to pro-opiomelanocortin (POMC) cleavage to produce alpha-melanocyte-stimulating hormone (α-MSH).
CONCLUSIONS: This study identified AST-DHA as an enhancer of autophagy that plays a beneficial role in restoring hypothalamic autophagy, and as a new potential therapeutic agent against HFD-induced obesity. © 2023 Society of Chemical Industry.

Agouti-related protein (AgRP) is a neuropeptide synthesized by AgRP/NPY neurons and transcribed as 132 amino acids in humans and 142 amino acids (AgRP1) in Japanese seabass (Lateolabrax maculatus) fish. AgRP neurons are activated by hormonal signals of energy deficits and inhibited by signals of energy surpluses and have been demonstrated to have the ability to sense the dynamics of blood glucose concentrations as the \"glucose sensor\" in mammals. It is widely recognized that AgRP is an endogenous antagonist of the melanocortin-3 and -4 receptors (MC3R and MC4R) in the hypothalamus, exhibiting potent orexigenic activity and control of energy homeostasis. Most fish, especially carnivorous fish, cannot make efficient use of carbohydrates. When carbohydrates like corn or wheat bran are added as energy sources, they often cause feeding inhibition and metabolic diseases. When fishmeal is replaced by plant protein, this does not completely eliminate carbs, limiting the utilization of carbohydrates and plant proteins in aquaculture. Our previous study showed that AgRP, and not neuropeptide Y (NPY) is the principal protein molecule that correlates well with feeding behavior in Japanese seabass from anorexia to adaptation. The Ghrelin/Leptin-mTOR-S6K1-NPY/AgRP/POMC feed intake regulatory pathway responds to the plant-oriented protein which contains glucose. However, its regulatory function and mechanism are still not clear. This review offers an integrative overview of how glucose signals converge on a molecular level in AgRP neurons of the arcuate nucleus of the hypothalamus. This is in order to control fish food intake and energy homeostasis.

α-Melanocyte-stimulating hormone (α-MSH) is a well-studied neuropeptide controlling skin and hair color. Besides, numerous immunomodulation roles of α-MSH were recorded in humans and mice. However, the regulatory effects of α-MSH in teleost immunity haven\'t been well elucidated. In this study, several precursor molecules of α-MSH (POMCs) and its receptors (MCRs) in Nile tilapia (Oreochromis niloticus) were characterized, and their expression characteristics and specific functions on antibacterial immunity were determined. Overall, POMCs and MCRs were principally detected in the brain, skin, and liver, and were remarkably promoted post Streptococcus agalactiae infection. However, tiny POMCs and MCRs were observed in tilapia immune organs (head kidney and spleen) or lymphocytes, and no evident immunomodulation effect was detected in vitro. Moreover, the in vivo challenge experiments revealed that α-MSH protects tilapia from bacterial infection by regulating responses in the brain and intestine. This study lays theoretical data for a deeper comprehension of the immunomodulation mechanisms of teleost α-MSH and the evolutional process of the vertebrate melanocortin system.

In teleost, as in other vertebrates, stress affects reproduction. A key component of the stress response is the pituitary secretion of the adrenocorticotropic hormone (ACTH), which binds to the melanocortin 2 receptor (MC2R) in the adrenal glands and activates cortisol biosynthesis. In zebrafish, Mc2r was identified in male and female gonads, while ACTH has been shown to have a physiological role in modulating reproductive activity. In this study, the hypothesis that other melanocortins may also affect how the zebrafish gonadal function is explored, specifically steroid biosynthesis, given the presence of members of the melanocortin signaling system in zebrafish gonads. Using cell culture, expression analysis, and cellular localization of gene expression, our new observations demonstrated that melanocortin receptors, accessory proteins, antagonists, and agonists are expressed in both the ovary and testis of zebrafish (n = 4 each sex). Moreover, melanocortin peptides modulate both basal and gonadotropin-stimulated steroid release from zebrafish gonads (n = 15 for males and n = 50 for females). In situ hybridization in ovaries (n = 3) of zebrafish showed mc1r and mc4r in follicular cells and adjacent to cortical alveoli in the ooplasm of previtellogenic and vitellogenic oocytes. In zebrafish testes (n = 3), mc4r and mc1r were detected exclusively in germ cells, specifically in spermatogonia and spermatocytes. Our results suggest that melanocortins are, directly or indirectly, involved in the endocrine control of vitellogenesis in females, through modulation of estradiol synthesis via autocrine or paracrine actions in zebrafish ovaries. Adult zebrafish testes were sensitive to low doses of ACTH, eliciting testosterone production, which indicates a potential role of this peptide as a paracrine regulator of testicular function.

Primary hyperparathyroidism (PHPT) is mainly caused by parathyroid adenoma, which produces excess parathyroid hormones. Its pathogenic mechanisms have not yet been fully understood. To investigate the mechanism in the pathogenesis of PHPT, the transcriptome and genome-wide DNA methylation profiles of parathyroid adenoma were analyzed. The candidate genes that may be involved in the PHPT were verified via qRT-PCR, immunohistochemistry, western blot, and methylation-specific PCR. A total of 1650 differentially expressed genes and 2373 differentially methylated regions were identified. After the integration of its transcriptome and DNA methylation data, IL6, SYP, GNA01, and pro-opiomelanocortin (POMC) were the candidate genes that demonstrated a similar pattern between their mRNA expression and DNA methylation status. Of the 4 candidate genes, POMC, a pro-peptide which is processed to a range of bioactive peptide products like ACTH, was further confirmed to be expressed at low levels at both the mRNA and protein levels, which may be due to POMC promoter hypermethylation. Hypermethylation of the POMC promoter may contribute to its low expression, which may be involved in the pathogenesis of PHPT.