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One of the major challenges the scientific community faces today is the lack of translational data generated from mouse trials for human health application. Housing temperature-dependent chronic cold stress in laboratory rodents is one of the key factors contributing to lack of translatability because it reveals major metabolic differences between humans and rodents. While humans tend to operate at temperatures within their thermoneutral zone, most laboratory rodents are housed at temperatures below this zone and have an increased energy demand to generate heat. This has an impact on the immune system of mice and thus affects results obtained using murine models of human diseases. A limited number of studies and reviews have shown that results obtained on mice housed at thermoneutrality were different from those obtained from mice housed in traditional housing conditions. Most of those studies, focused on obesity and cancer, found that housing mice at thermoneutrality changed the outcomes of the diseases negatively and positively, respectively. In this review, we describe how thermoneutrality impacts the immune system of rodents generally and in the context of different disease models. We show that thermoneutrality exacerbates cardiovascular and auto-immune diseases; alleviates asthma and Alzheimer’s disease; and, changes gut microbiome populations. We also show that thermoneutrality can have exacerbating or alleviating effects on the outcome of infectious diseases. Thus, we join the call of others in this field to urge researchers to refine murine models of disease and increase their translational capacity by considering housing at thermoneutrality for trials involving rodents.

Obesity increases the risk for breast cancer and is associated with poor outcomes for cancer patients. A variety of rodent models have been used to investigate these relationships; however, key differences in experimental approaches, as well as unique aspects of rodent physiology lead to variability in how these valuable models are implemented. We combine expertise in the development and implementation of preclinical models of obesity and breast cancer to disseminate effective practices for studies that integrate these fields. In this review, we share, based on our experience, key considerations for model selection, highlighting important technical nuances and tips for use of preclinical models in studies that integrate obesity with breast cancer risk and progression. We describe relevant mouse and rat paradigms, specifically highlighting differences in breast tumor subtypes, estrogen production, and strategies to manipulate hormone levels. We also outline options for diet composition and housing environments to promote obesity in female rodents. While we have applied our experience to understanding obesity-associated breast cancer, the experimental variables we incorporate have relevance to multiple fields that investigate women’s health.

Body weight is a balance between energy intake and energy expenditure. Energy expenditure is mainly governed by physical activity and adaptive thermogenesis. Adaptive dietary thermogenesis in brown and beige adipose tissue occurs through mitochondrial uncoupling protein (UCP-1). Laboratory mice, when housed at an ambient temperature of 22–24 °C, maintain their body temperature by dietary thermogenesis, eating more food compared to thermoneutrality. Humans remain in the thermoneutral zone (TNZ) without expending extra energy to maintain normal body temperature. TRPV1 activation by capsaicin (CAP) inhibited weight gain in mice housed at ambient temperature by activating UCP-1-dependent adaptive thermogenesis. Hence, we evaluated the effect of CAP feeding on WT and UCP-1−/− mice maintained under thermoneutral conditions. Our research presents novel findings that TRPV1 activation by CAP at thermoneutrality counters obesity in WT mice and promotes PRDM-16-dependent UCP-1 transcription. CAP fails to inhibit weight gain in UCP-1−/− mice housed at thermoneutrality and in adipose tissue-specific PRDM-16−/− mice. In vitro, capsaicin treatment increases UCP-1 transcription in PRDM-16 overexpressing cells. Our data indicate for the first time that TRPV1 activation counters obesity at thermoneutrality permissive for UCP-1 and the enhancement of PRDM-16 is not beneficial in the absence of UCP-1.

Darwin's finches have been the focus of intense study demonstrating how climatic fluctuations coupled with resource competition drive the evolution of a variety of bill sizes and shapes. The bill, as other peripheral surfaces, also plays an important role in thermoregulation in numerous bird species. The avian bill is vascularized, while limbs have specialized vasculature that facilitate heat loss or heat conservation (i.e. they are thermoregulatory windows). The Galápagos Islands, home to Darwin's finches, have a hot and relatively dry climate for approximately half of the year, during which thermoregulatory windows (i.e. surfaces) could be important for thermoregulation and the linked challenge of water balance. We hypothesized that Darwin's finch bills have evolved in part for their role in thermoregulation, possibly co‐opted, following adaptation for other functions, such as foraging. We predicted that bills of Darwin's finches are effective thermoregulatory windows, and that species differences in bill morphology, along with physiology and behaviour, lead to differences in thermoregulatory function. To test these hypotheses, we conducted a field study to assess heat exchange and microclimate use in three ground finch species and sympatric cactus finch (Geospiza spp.). We collected thermal images of free‐living birds during a hot and dry season and recorded microclimate data for each observation. We used individual thermographic data to model the contribution of bills, legs and bodies to overall heat balance and compared surface temperatures to those from dead birds to test physiological control of heat loss from these surfaces. We derived and compared species‐specific threshold environmental temperatures, which are indicative of a species’ thermally neutral temperature. In all species, the bill surface was an effective heat dissipater during naturally occurring warm temperatures. As expected, we found that finches controlled surface temperatures through physiology and that young birds had higher surface temperatures than adults. Larger bills contributed proportionally more to overall heat loss than smaller bills. We demonstrate here that related, sympatric species with different bill sizes exhibit different patterns in the use of these thermoregulatory structures, supporting a role for thermoregulation in the evolution and ecology of Darwin's finch morphology. A plain language summary is available for this article. Plain Language Summary

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as the presence of hepatic steatosis in addition to one of three metabolic conditions: overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. Chronic exposure to excess dietary fatty acids may cause hepatic steatosis and metabolic disturbances. The alteration of the quality of mitochondria is one of the factors that could contribute to the metabolic dysregulation of MAFDL. This study was designed to determine, in a rodent model of MAFLD, the effects of a long-term high-fat diet (HFD) on some hepatic processes that characterize mitochondrial quality control, such as biogenesis, dynamics, and mitophagy. To mimic the human manifestation of MAFLD, the rats were exposed to both an HFD and a housing temperature within the rat thermoneutral zone (28–30 °C). After 14 weeks of the HFD, the rats showed significant fat deposition and liver steatosis. Concomitantly, some important factors related to the hepatic mitochondrial quality were markedly affected, such as increased mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) damage; reduced mitochondrial biogenesis, mtDNA copy numbers, mtDNA repair, and mitochondrial fusion. HFD-fed rats also showed an impaired mitophagy. Overall, the obtained data shed new light on the network of different processes contributing to the failure of mitochondrial quality control as a central event for mitochondrial dysregulation in MAFLD.

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a “fast food” diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.

Background Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown. Methods Colon 26 carcinoma (C26)‐bearing and PBS‐inoculated (Ctrl) mice were housed at standard (ST; 20°C–22°C) or thermoneutral temperature (TN; 28°C–32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays. Results C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (−35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (−40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3‐fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (−78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (−93% and −63%, p < 0.0044 vs. Ctrls). Cancer‐driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (−23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF‐15 and IL‐6 increased in all C26 mice (4‐fold, p < 0.009 vs. Ctrls), with a greater effect on IL‐6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2‐fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4‐fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (−44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2‐fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (−59%, p = 0.0213 vs. TN Ctrl). Conclusions In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer‐induced alterations in glucose metabolism and systemic responses.

Animal welfare and productive performance are compromised when animals are housed in environments which place them outside their thermal comfort zone. However, the identification of thermal stress, when based on air properties, suggests the use of outdated and generic indices. The objective of this work was to develop and validate a methodology for classifying and diagnosing heat stress in production animals based on psychrometric air relations. The model was created for broilers, pigs, dairy cattle, and laying birds, categorized into a total of 21 breeding phases. For each phase, a bibliographic search was carried out for the psychrometric parameters of the air—dry bulb temperature (AT) and relative humidity (RH)—that satisfied the animals’ critical and ideal thermoneutral zones. Adding the local atmospheric pressure (AP), the parameters were used to calculate the enthalpy (h), resulting in five comfort ranges. Based on this, a decision tree was elaborated, consisting of three attributes (AT, RH, and h) and seven diagnostic classes, based on the psychrometric principles of air. The proposed methodology was used in a case study, with a database extracted from an individual shelter for calves. For the evaluation of the decision tree, two induction algorithms, ID3 and c4.5, were compared, both of which presented high accuracy and proposed simpler tree models than the one theoretically developed for the methodology. In conclusion, the methodology represents a great potential to characterize the thermal comfort of the animals, diagnose the causes of stress, and recommend possible corrective actions. The study revealed that decision trees can be adapted and simplified for each creation phase.

PurposeDuring obesity, the adipose tissue is usually infiltrated by immune cells which are related to hallmarks of obesity such as systemic inflammation and insulin resistance (IR). Green tea (GT) has been widely studied for its anti-inflammatory actions, including the modulation in the proliferation and activity of immune cells, in addition to preventing cardiovascular and metabolic diseases.MethodsThe aim of the present study was to analyze the population of immune cells present in the subcutaneous and epididymal white adipose tissue (WAT) of mice kept at thermoneutrality (TN) and fed with a high-fat diet (HFD) for 16 weeks, supplemented or not with GT extract (500 mg/kg/12 weeks).ResultsThe HFD in association with TN has induced chronic inflammation, and IR in parallel with changes in the profile of immune cells in the subcutaneous and epidydimal WAT, increasing pro-inflammatory cytokines release, inflammatory cells infiltration, and fibrotic aspects in WAT. On the other hand, GT prevented body weight gain, in addition to avoiding IR and inflammation, and the consequent tissue fibrosis, maintaining a lower concentration of cytokines and a profile of immune cells similar to the control mice, preventing the harmful modulations induced by both HFD and TN.ConclusionsGT beneficial effects in WAT abrogated the deleterious effects triggered by HFD and TN, maintaining all immune cells and fibrotic markers at the same level as in lean mice. These results place WAT immune cells population as a potential target of GT action, also highlighting the positive effects of GT in obese mice housed at TN.

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and β3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.