Control Of Energy Homeostasis Research Articles

Food for Thought: Leptin and Hippocampal Synaptic Function.

It is well documented that the endocrine hormone, leptin controls energy homeostasis by providing key signals to specific hypothalamic nuclei. However, our knowledge of leptin’s central actions has advanced considerably over the last 20 years, with the hippocampus now established as an important brain target for this hormone. Leptin receptors are highly localised to hippocampal synapses, and increasing evidence reveals that activation of synaptically located leptin receptors markedly impacts cognitive processes, and specifically hippocampal-dependent learning and memory. Here, we review the recent actions of leptin at hippocampal synapses and explore the consequences for brain health and disease.

From an Empty Stomach to Anxiolysis: Molecular and Behavioral Assessment of Sex Differences in the Ghrelin Axis of Rats.

Ghrelin, a stomach-produced hormone, is well-recognized for its role in promoting feeding, controlling energy homeostasis, and glucoregulation. Ghrelin’s function to ensure survival extends beyond that: its release parallels that of corticosterone, and ghrelin administration and fasting have an anxiolytic and antidepressant effect. This clearly suggests a role in stress and anxiety. However, most studies of ghrelin’s effects on anxiety have been conducted exclusively on male rodents. Here, we hypothesize that female rats are wired for higher ghrelin sensitivity compared to males. To test this, we systematically compared components of the ghrelin axis between male and female Sprague Dawley rats. Next, we evaluated whether anxiety-like behavior and feeding response to endogenous or exogenous ghrelin are sex divergent. In line with our hypothesis, we show that female rats have higher serum levels of ghrelin and lower levels of the endogenous antagonist LEAP-2, compared to males. Furthermore, circulating ghrelin levels were partly dependent on estradiol; ovariectomy drastically reduced circulating ghrelin levels, which were partly restored by estradiol replacement. In contrast, orchiectomy did not affect circulating plasma ghrelin. Additionally, females expressed higher levels of the endogenous ghrelin receptor GHSR1A in brain areas involved in feeding and anxiety: the lateral hypothalamus, hippocampus, and amygdala. Moreover, overnight fasting increased GHSR1A expression in the amygdala of females, but not males. To evaluate the behavioral consequences of these molecular differences, male and female rats were tested in the elevated plus maze (EPM), open field (OF), and acoustic startle response (ASR) after three complementary ghrelin manipulations: increased endogenous ghrelin levels through overnight fasting, systemic administration of ghrelin, or blockade of fasting-induced ghrelin signaling with a GHSR1A antagonist. Here, females exhibited a stronger anxiolytic response to fasting and ghrelin in the ASR, in line with our findings of sex differences in the ghrelin axis. Most importantly, after GHSR1A antagonist treatment, females but not males displayed an anxiogenic response in the ASR, and a more pronounced anxiogenesis in the EPM and OF compared to males. Collectively, female rats are wired for higher sensitivity to fasting-induced anxiolytic ghrelin signaling. Further, the sex differences in the ghrelin axis are modulated, at least partly, by gonadal steroids, specifically estradiol. Overall, ghrelin plays a more prominent role in the regulation of anxiety-like behavior of female rats.

152-OR: Evidence Linking Loss of Hypothalamic Perineuronal Nets to Obesity Pathogenesis

Defective neurocircuit activity within the hypothalamic arcuate nucleus (ARC) , a crucial brain area for the regulation of metabolism, is implicated in obesity pathogenesis. Perineuronal nets (PNNs) are extracellular matrix structures that regulate neurocircuit activity, and PNN loss can adversely influence the activity of the enmeshed neurons. To determine if defective ARC PNNs might contribute to obesity, we first quantified PNN abundance in obese mice induced by consuming a high-fat high-sucrose diet (HFHS; Bio-Serv #F4997) 12 wk. We found that compared to chow-fed controls, HFHS diet feeding caused an 84.3% decrease (p<0.0001) in the abundance of PNNs enmeshing ARC neurons. This loss was also associated with increases of ARC microgliosis (1.5-fold; p=0.004) and astrogliosis (2.9-fold; p=0.006) , suggesting a link between ARC PNN loss and glial activation. To translate these findings to humans, we analyzed postmortem hypothalamic samples from 9 subjects (Sex, 7M/2F; Age, 22-71y) that had previously undergone quantitative T2 magnetic resonance imaging (MRI) to assess obesity-associated hypothalamic gliosis. Consistent with our findings in mice, ARC PNN content was strongly and inversely correlated with the hypothalamic gliosis score measured by T2-weighted MRI imaging (R2=0.63, p=0.01) . To assess whether this depletion of ARC PNNs might contribute to obesity, we microinjected either the PNN-digesting enzyme, ChABC, or heat-inactivated ChABC control, into the rat ARC at the onset of a 4 wk HFHS dietary intervention. We found that compared to controls, the magnitude of diet-induced hyperphagia (17%; p<0.0001) , weight gain (41%; p<0.0001) , and excess body fat accumulation (28%; p=0.01) increased following PNN digestion, driven largely by increased dark cycle food intake (24%; p=0.006) . These findings collectively identify ARC PNNs as novel participants in the central control of energy homeostasis, and implicate their loss as a potential contributor to obesity pathogenesis. Disclosure K.M.Alonge: None. G.J.Morton: Research Support; Novo Nordisk A/S. E.Schur: None. J.Thaler: None. M.W.Schwartz: None. M.D.Dorfman: None. J.M.Scarlett: None. S.J.Melhorn: None. Y.Ye: None. S.J.W.Hu: None. K.L.Francis: None. A.Hendrickson: None. K.Cui: None. Funding AG066509DK017047AG074152DK101997DK720269

Characterization of the metabolic differences between male and female C57BL/6 mice

AimsThe present study aims to compare the responses between male and female C57BL/6 mice to multiple metabolic challenges to understand the importance of sex in the control of energy homeostasis. Main methodsMale and female C57BL/6 mice were subjected to nutritional and hormonal challenges, such as food restriction and refeeding, diet-induced obesity, feeding response to ghrelin and leptin, ghrelin-induced growth hormone secretion, and central responsiveness to ghrelin and leptin. The hypothalamic expression of transcripts that control energy homeostasis was also evaluated. Key findingsMale mice lost more weight and lean body mass in response to food restriction, compared to females. During refeeding, males accumulated more body fat and exhibited lower energy expenditure and glycemia, as compared to females. Additionally, female mice exhibited a higher protection against diet-induced obesity and related metabolic imbalances in comparison to males. Low dose ghrelin injection elicited higher food intake and growth hormone secretion in male mice, whereas the acute anorexigenic effect of leptin was more robust in females. However, the sex differences in the feeding responses to ghrelin and leptin were not explained by variations in the central responsiveness to these hormones nor by differences in the fiber density from arcuate nucleus neurons. Female, but not male, mice exhibited compensatory increases in hypothalamic Pomc mRNA levels in response to diet-induced obesity. SignificanceOur findings revealed several sexually differentiated responses to metabolic challenges in C57BL/6 mice, highlighting the importance of taking into account sex differences in metabolic studies.

Loss of ciliary adenylyl cyclase 3 in the ventromedial hypothalamus resulted in a sex‐dependent obese phenotype

Obesity, a metabolic disorder characterized by an excessive accumulation of body fat, continues to be a major economic and health burden to the global populace, as it is the most significant risk factor for heart disease, diabetes, and hypertension. Genome‐wide association studies have identified several genes involved in obesity development, including ADCY3, a gene encoding for the enzyme adenylyl cyclase 3 (AC3). AC3 is a critical mediator of the cyclic adenosine monophosphate (cAMP) signaling pathway and is enriched in the primary cilium, a solitary immotile organelle protruding from most mammalian cells, including neurons. The primary cilia act as the cellular antenna to sense and relay changes in the extracellular microenvironment and mounting evidence support a role for the primary cilia as a critical regulator of the energy homeostasis. Patients carrying loss‐of‐function ADCY3variants are obese and are at increased risk of developing type II diabetes mellitus (T2DM). Consistently, whole‐body Adcy3knockout mice also develop obesity; however, the underlying mechanisms by which AC3 affects metabolic homeostasis remain unclear. Here, we examined the impact of AC3 loss within the ventromedial nucleus of hypothalamus (VMH), a brain region critical for coordinated control of energy and glucose homeostasis, on energy metabolism. We generated mice with VMH‐specific Adcy3loss (Adcy3SF‐1KO mice) by crossing SF‐1 Cre+ mice with Adcy3F/F mice and subjected them to metabolic phenotyping to assess energy balance and glucose homeostasis. We observed a sexually dimorphic effect on body weight under standard chow diet; male Adcy3SF‐1KO mice displayed normal body weight gain comparable to control littermates, whereas female Adcy3SF‐1KO mice gained a significant more weight compared to control littermates (Con 24.34g v KO 30.61g, p < 0.0001). Strikingly, however, both sexes of Adcy3SF‐1KOmice exhibited improved glucose tolerance (AUC: M Con 17,826 v KO 15,165, p = 0.02; F Con 15,263 v KO 13,238, p = 0.03) without affecting fed and overnight fasting blood glucose levels. Taken together, these results underscore the importance of AC3‐mediated ciliary cAMP signaling in VMH neurons for the regulation of energy balance and glucose homeostasis in a sex‐dependent manner.

Editorial: Neural Control of Energy Homeostasis and Energy Homeostasis Regulation of Brain Function

Editorial: Neural Control of Energy Homeostasis and Energy Homeostasis Regulation of Brain Function

Brown adipose tissue involution associated with progressive restriction in progenitor competence.

Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

Hepatic glycogen participates in the regulation of hypothalamic pAkt/Akt ratio in high-sugar/high-fat diet-induced obesity

The hypothalamus is a major integrating centre that controls energy homeostasis and plays a major role in hepatic glycogen (HGlyc) turnover. Not only do hypothalamic and hepatic Akt levels influence glucose homeostasis and glycogen synthesis, but exposure to high-sugar/high-fat diets (HSHF) can also lead to hypothalamic inflammation and HGlyc accumulation. HSHF withdrawal overall restores energy and glucose homeostasis, but the actual relationship between hypothalamic inflammation and HGlyc after short-term HSHF withdrawal has not yet been fully elucidated. Here we investigated the short-term effects of HSHF withdrawal preceded by a 30-day HSHF intake on the liver-hypothalamus crosstalk and glucose homeostasis. Sixty-day old male Wistar rats were fed for 30 days a control chow (n = 10) (Ct), or an HSHF diet (n = 20). On the 30th day of dietary intervention, a random HSHF subset (n = 10) had their diets switched to control chow for 48h (Hw) whilst the remaining HSHF rats remained in the HSHF diet (n = 10) (Hd). All rats were anaesthetized and euthanized at the end of the protocol. We quantified HGlyc, Akt phosphorylation, inflammation and glucose homeostasis biomarkers. We also assessed the effect of propensity to obesity on those biomarkers, as detailed previously. Hd rats showed impaired glucose homeostasis, higher HGlyc and hypothalamic inflammation, and lower pAkt/Akt. Increased HGlyc was significantly associated with HSHF intake on pAkt/Akt lowered levels. We also found that HGlyc breakdown may have prevented a further pAkt/Akt drop after HSHF withdrawal. Propensity to obesity showed no apparent effect on hypothalamic inflammation or glucose homeostasis. Our findings suggest a comprehensive role of HGlyc as a structural and functional modulator of energy metabolism, and such roles may come into play relatively rapidly.

Identification of Regions Involved in the Physical Interaction between Melanocortin Receptor Accessory Protein 2 and Prokineticin Receptor 2.

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an anorexic effect and modulates thermoregulation and energy homeostasis. In the present work, we used biochemical techniques to analyze the mechanism of interaction of MRAP2 with PKR2 and we identified the specific amino acid regions involved in the complex formation. Our results indicate that MRAP2 likely binds to the N-terminal region of PKR2, preventing glycosylation and consequently the correct receptor localization. We also identified a C-terminal region of MRAP2 that is critical for the interaction with PKR2. Consequently, we analyzed the role of the prokineticin transduction system in the regulation of MRAP2 expression in tissues involved in the control of food intake: at the central level, in hypothalamic explants, and at the peripheral level, in adipocytes. We demonstrated the modulation of MRAP2 expression by the prokineticin transduction system.

Effects of Galp and alarin peptides on HPA axis gene expression and adrenal function: In vivo experiments.

Many experimental data indicate interactions between peptides involved in the control of food intake, energy homeostasis and adrenocortical hormone release. Glucocorticoids stimulate or inhibit the secretion of orexigenic and anorexigenic peptides, which in turn are involved in the regulation of adrenal growth, structure and function. Galanin-like peptide (Galp) and alarin (Ala) are involved in the regulation of food intake. Galp and Ala mRNAs have already been shown to be present in the arcuate nucleus (ARC) of the hypothalamus in both rats and mice. To investigate the expression of Ala, Galp and their receptors in the hypothalamus and pituitary and adrenal glands of the rat hypothalamic-pituitary-adrenal (HPA) axis after intraperitoneal administration of peptides in vivo. Experimental in vivo models were used: acute and long-term exposure to peptides. The expression of Galp, Ala, their receptors, and steroidogenesis enzymes was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Statistically significant expression changes were found in the hypothalamus and pituitary after 1-hour exposure to the peptides, such as a decrease in corticotropin-releasing hormone (CRH) expression after Ala, Galp and adrenocorticotropic hormone (ACTH) administration, and a decrease in the expression of receptors for galanin (Gal) (Galr1 and Galr2). In the pituitary, there was a statistically significant increase in the expression of Ala, Galr1, Galr2, and Galr3 receptors 1 h after Galp administration. In the adrenal glands, only a statistically significant decrease in Galr2 expression was observed after 1 h of Ala 0.5 administration. The mRNA expression of steroidogenesis enzymes also changed: for example, the expression of cholesterol desmolase increased 24 h after Ala peptide administration. The results indicate that the peptides tested under in vivo conditions can alter the expression of the peptides tested, as well as of Galp, Ala and Gal receptors and steroidogenesis enzymes - Cyp11a1 (cholesterol desmolase), Cyp11b1 (11β-hydroxylase) and Cyp11b2 (aldosterone synthase).

Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.

Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.

NPY derived from AGRP neurons controls feeding via Y1 and energy expenditure and food foraging behaviour via Y2 signalling

ObjectiveAguti-related protein (AGRP) neurons in the arcuate nucleus of the hypothalamus (ARC), which co-express neuropeptide Y (NPY), are key regulators of feeding and energy homeostasis. However, the precise role NPY has within these neurons and the specific pathways that it control are still unclear. In this article, we aimed to determine what aspects of feeding behaviour and energy homeostasis are controlled by NPY originating from AGRP neurons and which Y-receptor pathways are utilised to fulfil this function. MethodsNovel conditional Agrpcre/+;Npylox/lox knockout mice were generated and comprehensively phenotyped, both under standard chow as well as high-fat-diet conditions. Designer receptor exclusively activated by designer drugs (DREADD) technology was used to assess the altered responses on feeding and energy homeostasis control in the absence of NPY in these neurons. Rescue experiments utilising Npy1r- and Npy2r-selective NPY ligands were performed to assess which component of the energy homeostasis control is dependent by which specific Y-receptor pathway. ResultsWe show that the specific deletion of Npy only in AGRP neurons leads to a paradoxical mild obese phenotype associated with reduced locomotion and energy expenditure and increased feeding and Respiratory Quotient (RQ) that remain elevated under a positive energy balance. The activation of Npy-deficient AGRP neurons via DREADD's is still able to drive feeding, yet with a delayed onset. Additionally, Clozapine-N-oxide (CNO) treatment reduces locomotion without impacting on energy expenditure. Rescue experiments re-introducing Npy1r- and Npy2r-selective NPY ligands revealed that the increased feeding and RQ are mostly driven by Npy1r, whereas energy expenditure and locomotion are controlled by Npy2r signalling. ConclusionTogether, these results demonstrate that NPY originating from AGRP neurons is not only critical to initiate but also for continuously driving feeding, and we for the first time identify which Y-receptor controls which pathway.

Leptin in Dental Pulp and Periapical Tissues: A Narrative Review.

Leptin is a non-glycosylated 16 kDa protein synthesized mainly in adipose cells. The main function of leptin is to regulate energy homeostasis and weight control in a central manner. There is increasing evidence that leptin also has systemic effects, acting as a link between innate and acquired immune responses. The expression of leptin and its receptor in human dental pulp and periradicular tissues have already been described, as well as several stimulatory effects of leptin protein expression in dental and periodontal tissues. The aim of this paper was to review and to compile the reported scientific literature on the role and effects of leptin in the dental pulp and periapical tissues. Twelve articles accomplished the inclusion criteria, and a comprehensive narrative review was carried out. Review of the available scientific literature concluded that leptin has the following effects on pulpal and periapical physiology: 1) Stimulates odontogenic differentiation of dental pulp stem cells (DPSCs), 2) Increases the expression of dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1), odontoblastic proteins involved in odontoblastic differentiation and dentin mineralization, 3) Stimulates vascular endothelial growth factor (VEGF) expression in human dental pulp tissue and primary cultured cells of human dental pulp (hDPCs), 4) Stimulates angiogenesis in rat dental pulp cells, and 5) Induces the expression of interleucinas 6 and 8 in human periodontal ligament cells (hPDLCs). There is evidence which suggests that leptin is implicated in the dentin mineralization process and in pulpal and periapical inflammatory and reparative responses.

Nutritional Impact on Metabolic Homeostasis and Brain Health.

Aging in modern societies is often associated with various diseases including metabolic and neurodegenerative disorders. In recent years, researchers have shown that both dysfunctions are related to each other. Although the relationship is not fully understood, recent evidence indicate that metabolic control plays a determinant role in neural defects onset. Indeed, energy balance dysregulation affects neuroenergetics by altering energy supply and thus neuronal activity. Consistently, different diets to help control body weight, blood glucose or insulin sensitivity are also effective in improving neurodegenerative disorders, dampening symptoms, or decreasing the risk of disease onset. Moreover, adapted nutritional recommendations improve learning, memory, and mood in healthy subjects as well. Interestingly, adjusted carbohydrate content of meals is the most efficient for both brain function and metabolic regulation improvement. Notably, documented neurological disorders impacted by specific diets suggest that the processes involved are inflammation, mitochondrial function and redox balance as well as ATP production. Interestingly, processes involving inflammation, mitochondrial function and redox balance as well as ATP production are also described in brain regulation of energy homeostasis. Therefore, it is likely that changes in brain function induced by diets can affect brain control of energy homeostasis and other brain functions such as memory, anxiety, social behavior, or motor skills. Moreover, a defect in energy supply could participate to the development of neurodegenerative disorders. Among the possible processes involved, the role of ketone bodies metabolism, neurogenesis and synaptic plasticity, oxidative stress and inflammation or epigenetic regulations as well as gut-brain axis and SCFA have been proposed in the literature. Therefore, the goal of this review is to provide hints about how nutritional studies could help to better understand the tight relationship between metabolic balance, brain activity and aging. Altogether, diets that help maintaining a metabolic balance could be key to both maintain energy homeostasis and prevent neurological disorders, thus contributing to promote healthy aging.

Long-acting amylin analogues for the management of obesity.

To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to - at least partly - be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide. Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.

Mouse Microglial Calcitonin Receptor Knockout Impairs Hypothalamic Amylin Neuronal pSTAT3 Signaling but Lacks Major Metabolic Consequences.

Amylin and leptin synergistically interact in the arcuate nucleus of the hypothalamus (ARC) to control energy homeostasis. Our previous rodent studies suggested that amylin-induced interleukin-6 release from hypothalamic microglia may modulate leptin signaling in agouti-related peptide expressing neurons. To confirm the physiological relevance of this finding, the calcitonin receptor (CTR) subunit of the amylin receptor was selectively depleted in microglia by crossing tamoxifen (Tx) inducible Cx3cr1-CreERT2 mice with CTR-floxed mice. Unexpectedly, male mice with CTR-depleted microglia (KO) gained the least amount of weight of all groups regardless of diet. However, after correcting for the tamoxifen effect, there was no significant difference for body weight, fat mass or lean mass between genotypes. No alteration in glucose tolerance or insulin release was detected. However, male KO mice had a reduced respiratory quotient suggesting a preference for fat as a fuel when fed a high fat diet. Importantly, amylin-induced pSTAT3 was decreased in the ARC of KO mice but this was not reflected in a reduced anorectic response. On the other hand, KO mice seemed to be less responsive to leptin’s anorectic effect while displaying similar ARC pSTAT3 as Tx-control mice. Together, these data suggest that microglial amylin signaling is not a major player in the control of energy homeostasis in mice.

Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System.

The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.

Leptin gene contributes to beef marbling standard, meat brightness, meat firmness, and beef fat standard of the Kumamoto sub-breed of Japanese Brown cattle.

The Kumamoto sub-breed of Japanese Brown cattle has unique characteristics, such as great growth rate, and their contribution as future breeding materials is expected. To develop a DNA marker for their breeding, we investigated the effects of Leptin gene, controlling energy homeostasis, on carcass traits of the Kumamoto sub-breed. Sequence comparison identified five single nucleotide polymorphisms (SNPs): four linked synonymous mutations and one nonsynonymous mutation. Statistical analysis revealed that c.239C > T (p.A80V) had significant effects on the traits related with quality grade: beef marbling standard (p = 0.0132), meat brightness (p = 0.0383), and meat firmness (p = 0.0115). The C allele showed favorable effects; these scores of the C/C cattle were significantly higher than those of the C/T cattle. On the other hand, the effect of c.399T > C was observed on meat firmness (p = 0.0172) and beef fat standards (BFS) (p = 0.0129). The C/C cattle showed higher values of these traits than the T/T cattle. Our data suggested that these SNPs in Leptin gene could be used as a DNA marker for breeding of the Kumamoto sub-breed.

Metformin and the risk of dementia based on an analysis of 396,332 participants.

Background:AMPK has attracted widespread interest as a potential therapeutic target for age-related diseases, given its key role in controlling energy homeostasis. Metformin (Met) has historically been used to treat Type 2 diabetes and has been shown to counteract age-related diseases. However, studies regarding the relationship between Met and a variety of age-related classifications of cognitive decline have reported mixed findings.Objective:To assess the potential effect of Met on the onset of dementia and discuss the possible biological mechanisms involved.Methods:This study was registered in the PROSPERO database (CRD420201251468). PubMed, Embase, and Cochrane Library were searched from inception to 25 May 2021, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. Meta-regression and subgroup analyses were performed to explore sources of heterogeneity and the stability of the results.Results:Fourteen population-based cohort studies (17 individual comparisons) involving 396,332 participants were identified. Meta-analysis showed that Met exposure was significantly associated with reduced risk of all subtypes of dementias [relative risk (RR) = 0.79, 95% CI = 0.68–0.91; p < 0.001]. Conversely, no significant reduction in risk was observed for those who received Met monotherapy at the onset of vascular dementia (VD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). The effect was more prominent in patients who had long-term Met exposure (⩾4 years) (RR = 0.38, 95% CI = 0.32–0.46; p < 0.001), while no such significant effect was found with short-term Met exposure (1–2 years) (RR = 1.20, 95% CI = 0.87–1.66; p < 0.001). Moreover, no association was observed for Met exposure in participants of European descent (RR = 1.01, 95% CI = 0.66–1.54; p = 0.003) compared with those from other countries.Conclusion:Based on the evidence from population-based cohort studies, our findings suggest that the AMPK activator, Met, is a potential geroprotective agent for dementias, particularly among long-term Met users. Due to the significant heterogeneity among the included studies, we should interpret the results with caution.

Assessment of Ulva lactuca Extract on Inflammatory Markers in Fructose Fed Experimental Rats

Adipose tissue controls energy homeostasis. Adipocytes secrete hormones and inflammation-related adipokines in addition to storing fat. Green seaweeds are a typical dietary element in Eastern Asian nations like India. They are rich in proteins, vitamins, minerals, fibre, polyunsaturated fatty acids, and bioactive compounds. This study examined Ulva lactuca extract's influence on hormones and anti-inflammatory markers in fructose-fed rats. High fructose-fed rats had elevated blood leptin, IL-6, TNF-, and decreased adiponectin and ghrelin. Ulva lactuca extract improved leptin, IL-6, TNF-, adiponectin, and ghrelin in obese rats. Ulva lactuca may restore adipose tissue function owing to saponin, steroids, alkaloids, polyphenol, and glycoside