Thermoneutrality decreases thermogenic program and promotes adiposity in high-fat diet-fed mice

Abstract

Brown/beige adipocytes are therapeutic targets to combat obesity due to their abilities to dissipate energy through adaptive thermogenesis. Most studies investigating induction of brown/beige adipocytes were conducted in cold condition (e.g., 4°C); much is unknown about how the thermogenic program of brown/beige adipocytes is regulated in thermoneutral condition (e.g., 30°C), which is within the thermal comfort zone of human dwellings in daily life. Therefore, this study aims to characterize the thermogenic program of brown/beige adipocytes in mice housed under ambient (22°C) versus thermoneutral condition (30°C). Male mice raised at 22°C or 30°C were fed either chow diet or high‐fat (HF) diet for 20 weeks. Despite less food intake, chow‐fed mice housed at 30°C remained the same body weight compared to mice at 22°C. However, these thermoneutrally housed mice displayed a decrease in the expression of thermogenic program in both brown and white fat depots with larger adipocytes. When pair‐fed with chow diet, thermoneutrally housed mice showed an increase in body weight. Moreover, thermoneutrality increased body weight of mice fed with HF diet. This was associated with decreased expression of the thermogenic program in both brown and white fat depots of the thermoneutrally housed mice. The downregulation of the thermogenic program might have resulted from decreased sympathetic drive in the thermoneutrally housed mice evident by decreased expression of tyrosine hydroxylase expression and norepinephrine turnover in both brown and white fat depots. Our data demonstrate that thermoneutrality may negatively regulate the thermogenic program and sympathetic drive, leading to increased adiposity in mice.

Of mice and men – environmental temperature, body temperature, and treatment of obesity

“…Interestingly, housing mice at thermoneutrality causes increases adiposity (e.g., [43][44][45][46]). This propensity for obesity is poorly understood at the mechanistic level.…”

Brown adipose tissue remodelling induced by corticosterone in male Wistar rats

“…Therefore, adipose tissue's 'brownish' phenotype is associated with a favourable metabolic trait. On the other hand, thermoneutrality or obesity (genetic or high-fat diet-induced) leads to BAT's functional decline, unilocular rearrangement and increased leptin expression -'whitening' (Cui et al, 2016;Kotzbeck et al, 2018). In humans, there is an inverse relationship between BAT activity and body mass index (van Marken Lichtenbelt et al, 2009), suggesting a role for BAT in the pathophysiology of obesity.…”

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

“…We also performed HFD feeding in these animals under thermoneutrality (30ºC) to avoid any non-shivering thermogenesis that may be induced by mild cold stress in mice housed under ambient room temperature (20-22ºC) as we recently reported 45 , which may serve as a confounding factor in assessing diet-induced thermogenesis 4,46,47 . When housed at thermoneutrality, HFD-fed TRKC+/-mice consistently gained more weight (Fig 6H) and had increased fat mass in iBAT, iWAT and eWAT (Fig 6I) with larger adipocytes sizes (Suppl.…”

“…TRKC+/-, STRKCKO, AdNTF3-Tg mice and their respective littermate controls were fed either low fat (LF) (Research Diets D12450B, 10% calorie from fat) or high fat (HF) (Research Diets D12492, 60% calorie from fat) diet for up to 20 weeks. Some experiments were conducted under thermoneutrality (30ºC) to avoid any non-shivering thermogenesis that may be induced by mild cold stress in mice housed under ambient room temperature (20-22ºC) as we recently reported 45 , which may serve as a confounding factor in assessing diet-induced thermogenesis 4,46 . Various metabolic phenotypes were characterized as follows.…”