Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Abstract

Background and aim:Rodents are commonly housed below thermoneutrality and this exposure to 'cold' (i.e. 20°C) activates thermogenic brown (BAT) and beiging of white adipose tissue. Here, we examined whether a standard housing temperature (i.e. 20°C, a reduction in temperature of ~8°C) or YM-178, a highly-selective β 3-adrenoreceptor agonist, in obese animals raised at thermoneutrality, would impact differently on classical BAT or subcutaneous inguinal (IWAT) beige depots. Methods: Eighteen weanling Sprague-Dawley rats were housed at thermoneutrality (28°C) and fed a high-fat diet. At 12 weeks, 6 animals were randomised to either standard housing temperature (20°C, n=6) or to β 3-AR agonist administration (28°C+β3, 0.75mg/kg/d, n=6) for 4 weeks. Metabolic assessment was undertaken during the final 48h, followed by interscapular, perivascular BAT and IWAT sampling for the analysis of thermogenic genes and the proteome. Results: Exposure to 20°C increased weight gain, BAT and IWAT mass. Proteomic analysis of BAT revealed novel pathways associated with cold-induced weight gain (i.e. histone deacetylation, glycosaminoglycan degradation and glycosphingolipid biosynthesis) whilst β 3adrenoreceptor agonism impacted on proteins involved in skeletal muscle contraction and cell differentiation. IWAT of cold-exposed animals exhibited an enrichment of proteins involved NAD+ binding, plus retinol and tyrosine metabolic pathways whilst β 3-AR agonism downregulated ribosomal and upregulated acute phase response proteins. Conclusion: Following diet-induced obesity at thermoneutrality, exposure to 20°C promotes subcutaneous fat deposition in order to reduce heat loss and defend body temperature. In contrast, chronic administration of β 3-AR agonist has minimal metabolic-related effects on adipose tissue.

Perivascular adipose tissue remodeling impairs vasoreactivity in thermoneutral-housed rats

“…Intriguingly, both male and female animals housed at TN weighed significantly less than those at RT. This is in contrast to other studies observing increased body weight gain in rodents exposed to cold temperatures from either RT housing or TN housing (44,45). Some studies show no difference in body weight between rats housed at RT and TN (46), while others show increased diet-dependent adiposity at TN temperatures (47).…”

Intermittent cold exposure improves glucose homeostasis despite exacerbating diet‐induced obesity in mice housed at thermoneutrality

“…In line with data from chronic mild cold exposure (Aldiss et al . 2021), ICE increased BAT, eWAT and iWAT, but not liver mass (Fig. 2– J ), independent of diet, suggesting that the ICE‐induced increases in body mass were largely a result of increases in adiposity.…”

“…Importantly, acute exposure from 30°C to 14°C elicits AgRP neuron activity both rapidly and in a reversible manner (Deem et al 2020), suggesting that the effects of ICE we observed on energy intake and subsequently on body mass are not secondary to an extreme difference in ambient temperatures (30°C to 4°C). Likewise, Aldiss et al (2021) recently demonstrated that when obese rats, previously housed at 28°C, are chronically exposed to a mild ambient cold stress (21°C), they too exhibit increased weight gain and adipose tissue accumulation. As such, neither intermittent, nor chronic ambient cold exposure, regardless of whether it is mild or severe in nature, appears to be an efficacious treatment for obesity.…”

“…Likewise, Aldiss et al . (2021) recently demonstrated that when obese rats, previously housed at 28°C, are chronically exposed to a mild ambient cold stress (21°C), they too exhibit increased weight gain and adipose tissue accumulation. As such, neither intermittent, nor chronic ambient cold exposure, regardless of whether it is mild or severe in nature, appears to be an efficacious treatment for obesity.…”

Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

“…In fact, we have recently demonstrated that when mice are housed at thermoneutrality and their BAT phenotype is humanized, 25 a physiologically relevant model of ambient cold exposure causes rapid and persistent hyperphagia that exacerbates, rather than attenuates, diet‐induced obesity 26 . Similar reports are beginning to emerge 27 and thus it should be acknowledged that ambient cold exposure does not protect humanized rodents against diet‐induced obesity. As such, the identification of translationally relevant alternative treatment strategies is highly warranted.…”