Walnut supplementation increases levels of UCP1 and CD36 in brown adipose tissue independently of diet type.

Dietary interventions that modulate the brown adipose tissue (BAT) thermogenic activity could represent a promising therapy for metabolic disorders. In order to examine if dietary walnuts intake regulates the expression of BAT thermogenic markers levels in healthy and metabolically challenged (fructose fed) animals, rats were initially divided into the control and fructose-fed groups. After nine weeks, these groups were subdivided into the one kept on the original regimens and the other supplemented with walnuts. High-fructose diet resulted in an increased relative BAT mass and no change in UCP1 content, while the walnut supplementation increased the amount of UCP1 in BAT, but did not affect 5-HT, NA, DHPG content and DHPG/NA ratio regardless of the diet. Moreover, the CD36 levels were increased following the walnut consumption, unlike FATP1, GLUT1, GLUT4, and glycogen content which remained unchanged. Additionally, the BAT levels of activated IR and Akt were not affected by walnut consumption, while ERK signaling was decreased. Overall, we found that walnut consumption increased UCP1 and CD36 content in the BAT of both control and metabolically challenged rats, suggesting that FFAs represent the BAT preferred substrate under the previously described circumstances. This further implies that incorporating walnuts into the everyday diet may help to alleviate some symptoms of the metabolic disorder.

From Molecular Mechanisms to Clinical Therapy: Understanding Sepsis-Induced Multiple Organ Dysfunction.

Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future.

The Expression of Insulin in the Central Nervous System: What Have We Learned So Far?

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both insulin mRNA and insulin were detected in the central nervous system (CNS), it is now known that this hormone is also synthesized in several brain regions, including the hypothalamus, hippocampus, cerebral and cerebellar cortex, and olfactory bulb. Although many roles of insulin in the CNS have been described, it was initially unknown which of them could be attributed to brain-derived and which to pancreatic insulin or whether their actions in the brain overlap. However, more and more studies have been emerging lately, focusing solely on the roles of brain-derived insulin. The aim of this review was to present the latest findings on the roles of brain-derived insulin, including neuroprotection, control of growth hormone secretion, and regulation of appetite and neuronal glucose uptake. Lastly, the impairment of signaling initiated by brain-derived insulin was addressed in regard to memory decline in humans.

The Effects of a Meldonium Pre-Treatment on the Course of the LPS-Induced Sepsis in Rats.

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment.

The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats.

Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.

Rat brown adipose tissue thermogenic markers are modulated by estrous cycle phases and short-term fasting.

Brown adipose tissue (BAT) converts chemical energy into heat to maintain body temperature. Although fatty acids (FAs) represent a primary substrate for uncoupling protein 1 (UCP1)-dependent thermogenesis, BAT also utilizes glucose for the same purpose. Considering that estrous cycle effects on BAT are not greatly explored, we examined those of 6-h fasting on interscapular BAT (iBAT) thermogenic markers in proestrus and diestrus. We found that the percentage of multilocular adipocytes was lower in proestrus than in diestrus, although it was increased after fasting in both analyzed estrous cycle stages. Furthermore, the percentage of paucilocular adipocytes was increased by fasting, unlike the percentage of unilocular cells, which decreased in both analyzed stages of the estrous cycle. The UCP1 amount was lower in proestrus irrespectively of the examined dietary regimens. Regarding FA transporters, it was shown that iBAT CD36 content was increased in fasted rats in diestrus. In contrast to GLUT1, the level of GLUT4 was interactively modulated by selected estrous cycle phases and fasting. There was no change in insulin receptor and ERK1/2 activation, while AKT activation was interactively modulated by fasting and estrous cycle stages. Our study showed that iBAT exhibits morphological and functional changes in proestrus and diestrus. Moreover, iBAT undergoes additional dynamic functional and morphological changes during short-term fasting to modulate nutrient utilization and adjust energy expenditure.

Hypothalamic insulin expression remains unaltered after short-term fasting in female rats.

PURPOSE: Our previous study showed that 6-h fasting increased insulin expression in the hypothalamus of male rats. We, therefore, wanted to examine if this phenomenon occurs in female rats and whether it depended on the estrus cycle phase. METHODS: Female rats in proestrus or diestrus were either exposed to 6-h fasting or had ad libitum access to food. The serum, cerebrospinal fluid, and hypothalamic insulin levels were determined using radioimmunoassay. The hypothalamic insulin mRNA expression was measured by RT-qPCR, while the hypothalamic insulin distribution was assessed immunohistochemically. RESULTS: Albeit the short-term fasting lowered circulating insulin, both hypothalamic insulin mRNA expression and hypothalamic insulin content remained unaltered. As for the hypothalamic insulin distribution, strong insulin immunopositivity was noted primarily in ependymal cells lining the upper part of the third ventricle and some neurons mainly located within the periventricular nucleus. The pattern of insulin distribution was similar between the controls and the females exposed to fasting regardless of the estrous cycle phase. CONCLUSION: The findings of this study indicate that the control of insulin expression in the hypothalamus differs from that in the pancreatic beta cells during short-term fasting. Furthermore, they also imply that the regulation of insulin expression in the female hypothalamus is different from males but independent of the estrus cycle phase.