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INTRODUCTION We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle‐aged adults. METHODS We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme‐linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS Higher sOB‐R was associated with lower fractional anisotropy (FA, β = −0.114 ± 0.02, p < 0.001), and higher free water (FW, β = 0.091 ± 0.022, p < 0.001) and peak‐width skeletonized mean diffusivity (PSMD, β = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (β = 0.115 ± 0.027, p < 0.001) and lower FW (β = ‐0.096 ± 0.029, p = 0.001) and PSMD (β = ‐0.085 ± 0.028, p = 0.002). DISCUSSION Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle‐aged adults, supporting the putative neuroprotective role of leptin in late‐life dementia risk. Highlights Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks 1 – 4 . Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues 5 – 9 . However, the systemic impact of the gut microbiome on the germline—and consequently on the F 1 offspring it gives rise to—is unexplored 10 . Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut–germline axis’ in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function. Disturbances in the gut microbiota of male mice manifest as fitness defects in their offspring by affecting plancenta function, revealing a paternal gut–germline axis.

Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. Here, we show that the activity of the circadian clock regulator Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice.While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition, to direct the transcriptional regulation of metabolic programs by BMAL1, we show that the disruption of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans but were absent in hepatocyte-specific Bmal1 knockout mice. This suggests that systemic endocrine perturbation associated with the global disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases.

Obesity has been linked to an increased risk of and a worse prognosis for several types of cancer. A number of interrelated mediators contribute to obesity’s pro-tumor effects, including chronic adipose inflammation and other perturbations of immune cell development and function. Here, we review studies examining the impact of obesity-induced immune dysfunction on cancer risk and progression. While the role of adipose tissue inflammation in obesity-associated cancer risk has been well characterized, the effects of obesity on immune cell infiltration and activity within the tumor microenvironment are not well studied. In this review, we aim to highlight the impact of both adipose-mediated inflammatory signaling and intratumoral immunosuppressive signaling in obesity-induced cancer risk, progression, and metastasis.

Background/ObjectivesAlteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated.MethodsWe used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice.ResultsPostnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin.ConclusionsEarly postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.

•Polycystic ovarian syndrome causes impaired metabolic switch in skeletal muscle.•Impaired metabolic switch is mediated by elevated PDK4.•Acetate restores metabolic switch in skeletal muscle of animals with polycystic ovarian syndrome .•The beneficial effect of acetate is accompanied by suppressed PDK4/NLRP3. Endocrine disorders in women of childbearing age, including polycystic ovarian syndrome (PCOS), have been linked to skeletal muscle insulin resistance with multiple post-receptor intracellular defects, disrupting metabolic flexibility. Short-chain fatty acids, such as acetate have been suggested as a metabolic modulator. However, the effects of acetate on aberrant metabolic switch in skeletal muscle of individuals with PCOS are unknown. This study therefore hypothesized that acetate would circumvent impaired metabolic switch in the skeletal muscle of a letrozole-induced PCOS rat model, probably by suppression of PDK4/NLRP3. Methods: Eight-wk-old female Wistar rats were assigned into three groups (n = 6), which received vehicle, letrozole (1 mg/kg), and letrozole plus acetate (200 mg/kg), respectively. The administrations were done by oral gavage for 21 d. . Animals with PCOS had insulin resistance, increased testosterone, and leptin, as well as decreased adiponectin level. Additionally, the skeletal muscle was also characterized with increased lipid deposition, malondialdehyde, inflammatory mediators (nuclear factor-κB and tumor necrosis factor-α), lactate dehydrogenase, lactate/pyruvate ratio, HDAC and PDK 4 with corresponding decrease in glycogen synthesis, glutathione and NrF2. Besides, immunohistochemical evaluation showed severe expression of inflammasome and apoptosis in PCOS animals. Nonetheless, supplementation with acetate significantly attenuated these perturbations. The present results demonstrate aberrant metabolic switch in the skeletal muscle of PCOS animals, which is accompanied by excessive inflammation, oxidative stress and elevated levels of histone deacetylase and PDK4. The results suggested that histone deacetylase inhibitor, acetate circumvents impaired metabolic switch in the skeletal muscle of PCOS rats by suppression of PDK4/NLRP3 inflammasome.

Phasic dopamine release from mid-brain dopaminergic neurons is thought to signal errors of reward prediction (RPE). If reward maximisation is to maintain homeostasis, then the value of primary rewards should be coupled to the homeostatic errors they remediate. This leads to the prediction that RPE signals should be configured as a function of homeostatic state and thus diminish with the attenuation of homeostatic error. To test this hypothesis, we collected a large volume of functional MRI data from five human volunteers on four separate days. After fasting for 12 hours, subjects consumed preloads that differed in glucose concentration. Participants then underwent a Pavlovian cue-conditioning paradigm in which the colour of a fixation-cross was stochastically associated with the delivery of water or glucose via a gustometer. This design afforded computation of RPE separately for better- and worse-than expected outcomes during ascending and descending trajectories of serum glucose fluctuations. In the parabrachial nuclei, regional activity coding positive RPEs scaled positively with serum glucose for both ascending and descending glucose levels. The ventral tegmental area and substantia nigra became more sensitive to negative RPEs when glucose levels were ascending. Together, the results suggest that RPE signals in key brainstem structures are modulated by homeostatic trajectories of naturally occurring glycaemic flux, revealing a tight interplay between homeostatic state and the neural encoding of primary reward in the human brain.

BackgroundUnlike in other mouse models of atherogenesis, it has recently been suggested that orchiectomy plays a role in attenuating atherosclerosis and inhibiting the progression of cardiovascular disease in the ApoE−/−:Ins2+/Akita mouse model of hyperglycemia. Androgen-deprivation therapy (ADT) is a common treatment for prostate cancer, a population with high prevalence of cardiovascular disease and its risk factors. Our objectives were to test and further characterize the effects of pharmacological castration which is currently the acceptable modality to deliver ADT in the clinic.MethodsMale ApoE−/−:Ins2+/Akita mice received one of three modes of ADT (gonadotropin-releasing hormone (GnRH)-antagonist (degarelix), GnRH-agonist (leuprolide), or bilateral orchiectomy) and were compared to corresponding untreated control mice (n = 9–13/group). Mice were followed for 5 months. Body weight, fasting blood glucose, glucose tolerance, serum C-peptide, leptin, and testosterone levels along with atherosclerotic aortic plaque size and characteristics were determined. In a separate experiment, the survival of mice, untreated and on ADT, was determined.ResultsCastration was achieved for all three modes of ADT. However, degarelix-treated mice gained significantly less weight, had lower serum leptin levels and systolic blood pressure compared to orchiectomy and leuprolide-treated mice. ADT improved dysglycemia and atherosclerotic burden. GnRH-antagonist significantly improved survival compared to GnRH-agonist but not compared to orchiectomy.ConclusionsFurther characterization of the ApoE−/−:Ins2+/Akita mouse model confirms that pharmacological ADT ameliorated metabolic syndrome and cardiovascular complications. Improved dysglycemia and atherosclerosis associated with increased survival which was longest after degarelix followed by orchiectomy.