Cold Exposure and the Metabolism of Mice, Men, and Other Wonderful Creatures.

Laboratory rodents and cold-adapted animals in the wild use a significant amount of the energy derived from food intake for heat generation. Thermogenesis involving mitochondrial uncoupling in the brown adipose tissue differs quantitatively in mice, humans, and cold-adapted animals and could be an important ally to combat obesity if humans were prepared to deviate slightly from thermoneutral living conditions to activate this pathway.

Cold exposure aggravates pulmonary arterial hypertension through increased miR-146a-5p, miR-155-5p and cytokines TNF-α, IL-1ß, and IL-6.

BACKGROUND: Cold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored. AIM: To explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model. METHODS: Male Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR. RESULTS: The MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1ß, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group. CONCLUSION: Cold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.

Overheating or overcooling: heat transfer in the spot to fight against the pandemic obesity.

The prevalence of obesity has nearly doubled worldwide over the past three and a half decades, reaching pandemic status. Obesity is associated with decreased life expectancy and with an increased risk of metabolic, cardiovascular, nervous system diseases. Hence, understanding the mechanisms involved in the onset and development of obesity is mandatory to promote planned health actions to revert this scenario. In this review, common aspects of cold exposure, a process of heat generation, and exercise, a process of heat dissipation, will be discussed as two opposite mechanisms of obesity, which can be oversimplified as caloric conservation. A common road between heat generation and dissipation is the mobilization of Free Faty Acids (FFA) and Carbohydrates (CHO). An increase in energy expenditure (immediate effect) and molecular/metabolic adaptations (chronic effect) are responses that depend on SNS activity in both conditions of heat transfer. This cycle of using and removing FFA and CHO from blood either for heat or force generation disrupt the key concept of obesity: energy accumulation. Despite efforts in making the anti-obesity pill, maybe it is time to consider that the world's population is living at thermoneutrality since temperature-controlled places and the lack of exercise are favoring caloric accumulation.

Mild-cold water swimming does not exacerbate white adipose tissue browning and brown adipose tissue activation in mice.

The present study investigated the effects of swimming physical training either thermoneutral or below thermoneutral water temperature on white (WAT) and brown (BAT) adipose tissue metabolism, morphology, and function. C57BL/6J male mice (n = 40; weight 25.3 ± 0.1 g) were divided into control (CT30), cold control (CT20), trained (TR30), and cold trained (TR20) groups. Swimming training consisted of 30-min exercise at 30°C (control) or 20°C (cold) water temperature. After 8-week training, adipose tissues were excised and inguinal (ingWAT) and BAT were processed for histology, lipolysis, and protein contents of total OXPHOS, PGC1α, and UCP1 by western blotting analysis. Swimming training reduced body weight gain independently of water temperature (P < 0.05). ingWAT mass was decreased for TR30 in comparison to other groups (P < 0.05), while for BAT, there was a significant increase in CT20 in relation to CT30, and both trained groups were significantly increased in relation to control groups (P < 0.05). ingWAT mean adipocyte area was smaller for trained groups, and seemed to present multilocular adipocytes. Lipolytic activity and protein content of UCP1, PGC1α, and mitochondrial markers were increased in trained groups for ingWAT (P < 0.05), independent of water temperature (P > 0.05), and these patterns were not observed for BAT (P > 0.05). Our findings suggest that mild-cold water exposure and swimming physical exercise seem to, independently, promote browning in ingWAT with no effects on BAT; however, the association of exercise and mild-cold water did not exacerbate these effects.

Contribution of brown adipose tissue to human energy metabolism.

The present "obesogenic' environment has favored excessive energy intake resulting in the current obesity epidemic and its associated diseases. The epidemic has incentivized scientists to develop novel behavioral and pharmacological strategies that enhance energy expenditure to compensate for excessive energy intake. Although physical activity is effective to increase total energy expenditure, it is insufficient to induce negative energy balance and weight loss. With the discovery of brown adipose tissue (BAT) in adult humans, BAT activation soon emerged as a potential strategy for elevating energy expenditure. BAT is the only tissue that expresses uncoupling protein 1, conferring on this tissue high thermogenic capacity due to a low efficiency for mitochondrial ATP generation. Potential manipulation of BAT mass and activity has fueled the interest in altering whole-body energy balance through increased energy expenditure. Remarkable advances have been made in quantifying the amount and activity of BAT in humans. Many studies have concluded that the amount of active BAT appears insufficient to induce meaningful increases in energy expenditure. Thus, the majority of studies report that BAT activation does not influence body weight and metabolic control in humans. Strategies to increase BAT mass and/or to potentiate BAT activity seem necessary.

Interaction between the amount of dietary protein and the environmental temperature on the expression of browning markers in adipose tissue of rats.

BACKGROUND: A low-protein diet increases the expression and circulating concentration of FGF21. FGF21 stimulates the browning process of WAT by enhancing the expression of UCP1 coupled with an increase in PGC1α. Interestingly, the consumption of a low-protein diet could stimulate WAT differentiation into beige/brite cells by increasing FGF21 expression and Ucp1 mRNA abundance. However, whether the stimulus of a low-protein diet on WAT browning can synergistically interact with another browning stimulus, such as cold exposure, remains elusive. RESULTS: In the present study, rats were fed 6% (low), 20% (adequate), or 50% (high) dietary protein for 10 days and subsequently exposed to 4 °C for 72 h. Body weight, food intake, and energy expenditure were measured, as well as WAT browning and BAT thermogenesis markers and FGF21 circulating levels. The results showed that during cold exposure, the consumption of a high-protein diet reduced UCP1, TBX1, Cidea, Cd137, and Prdm16 in WAT when compared with the consumption of a low-protein diet. In contrast, at room temperature, a low-protein diet increased the expression of UCP1, Cidea, and Prdm16 associated with an increase in FGF21 expression and circulating levels when compared with a consumption of a high-protein diet. Consequently, the consumption of a low-protein diet increased energy expenditure. CONCLUSIONS: These results indicate that in addition to the environmental temperature, WAT browning is nutritionally modulated by dietary protein, affecting whole-body energy expenditure.

The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells.

Inclusions of phosphorylated tau (p-tau) are a hallmark of many neurodegenerative disorders classified as "tauopathy," of which Alzheimer's disease is the most prevalent form. Dysregulation of tau phosphorylation disrupts neuron structure and function, and hyperphosphorylated tau aggregates to form neurotoxic inclusions. The abundance of ubiquitin in tau inclusions suggests a defect in ubiquitin-mediated tau protein degradation by the proteasome. Under the temperature of 37 °C, the co-chaperone BAG2 protein targets phosphorylated tau for degradation via by a more-efficient, ubiquitin-independent pathway. In both in vivo and in vitro studies, cold exposure induces the accumulation of phosphorylated tau protein. The SH-SY5Y cell line differentiates into neuron-like cells on treatment with retinoic acid and is an established model for research on the effects of cold on tau phosphorylation. The aim of the present study was to investigate whether BAG2 mediates the cold-induced accumulation of phosphorylated tau protein. Our findings show that cold exposure causes a decrease in BAG2 expression in undifferentiated cells. Conversely, BAG2 expression is increased in differentiated cells exposed to cold. Further, undifferentiated cells exposed to cold had an increased proportion of p-tau to total tau, suggesting an accumulation of p-tau that is consistent with decreased levels of BAG2. Overexpression of BAG2 in cold-exposed undifferentiated cells restored levels of p-tau to those of 37 °C undifferentiated control. Interestingly, although BAG2 expression increased in differentiated cells, this increase was not accompanied by a decrease in the proportion of p-tau to total tau. Further, overexpression of BAG2 in cold exposed differentiated cells showed no significant difference in p-tau levels compared to 37 °C controls. Taken together, these data show that expression of BAG2 is differently regulated in a differentiation-dependent context. Our results suggest that repression of BAG2 expression or BAG2 activity by cold-sensitive pathways, as modeled in undifferentiated and differentiated cells, respectively, may be a causal factor in the accumulation of cytotoxic hyperphosphorylated tau protein via restriction of BAG2-mediated clearance of cellular p-tau.