Comparative Transcriptome Profiling of Young and Old Brown Adipose Tissue Thermogenesis

Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty acid. Therefore, the thermogenesis of BAT may be harnessed to treat obesity and related diseases. In mice and humans, BAT levels decrease with aging, and the underlying mechanism is elusive. Here, we compared the transcriptomic profiles of both young and aged BAT in response to thermogenic stimuli. The profiles were extracted from the GEO database. Intriguingly, aging does not cause transcriptional changes in thermogenic genes but upregulates several pathways related to the immune response and downregulates metabolic pathways. Acute severe CE upregulates several pathways related to protein folding. Chronic mild CE upregulates metabolic pathways, especially related to carbohydrate metabolism. Our findings provide a better understanding of the effects of aging and metabolic responses to thermogenic stimuli in BAT at the transcriptome level.

Dopaminergic Input from the Posterior Hypothalamus to the Raphe Pallidus Area Inhibits Brown Adipose Tissue Thermogenesis

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-OH-DPAT, in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of NMDA receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2R are expressed in cold-activated and serotonergic neurons in the rRPa and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pre-treatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically-active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Mechanisms in Endocrinology: LOCAL AND SYSTEMIC EFFECTS OF GLUCOCORTICOIDS ON METABOLISM: NEW LESSONS FROM ANIMAL MODELS

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

A potential role for endogenous oxytocin in adaptation to cold: implications for health?

Cold water swimming is thought to provide mental and physical health benefits, although the details of the potential signalling pathways involved in the body have not yet been fully established. We know that brown fat/brown adipose tissue is important in thermogenesis, thereby possibly helping in training the body to adapt to cold stimuli. As a result of brown adipose tissue thermogenesis during cold exposure, the body uses up the stored fat energy to produce heat energy. Such metabolism of fat can therefore help combat diseases associated with gain of fat, such as obesity and type 2 diabetes mellitus. Here, we present a potential role for oxytocin in stimulating brown adipose tissue thermogenesis during cold exposure and adaptation. We discuss cold adaptation and brown adipose tissue thermogenesis, and present our hypothesis for the role of oxytocin in cold adaptation and its perceived benefits for health.

Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.

A YY1 phosphorylation switch in brown adipose tissue orchestrates energy homeostasis.

Whole-body energy homeostasis is influenced by anabolic and catabolic cellular programs, which depend on environmental and nutritional cues. Adipose tissue plays a predominant role in the physiological regulation of energy balance by either storing or consuming energy through brown adipose tissue thermogenesis. It is however not clearly understood how brown adipose tissue balances catabolic and anabolic states. We show here that the transcription factor YY1 senses energetic state through a post-translational S120 phosphorylation switch. Adrenergic signaling leads to YY1 dephosphorylation which directly activates thermogenesis and a catabolic gene program while its phosphorylation maintains an anabolic program. Mechanistically, YY1 dephosphorylation increases chromatin binding at distal genomic loci respective to the transcription start site but remains constitutively bound to TSS. This mode of transcriptional control influences the activating and repressive function of YY1 and regulates catabolism/anabolism. We show that YY1 interacts with PPP1R3B, a regulatory subunit of the phosphatase PP1 and that in vivo knockdown of PPP1R3B protects against diet-induced obesity and insulin resistance. Our results uncover a novel transcriptional mechanism of metabolism orchestrated by YY1 phosphorylation switch and identifies PPP1R3B as a regulator of energy balance.

Alternative Polyadenylation and Differential Regulation of Ucp1: Implications for Brown Adipose Tissue Thermogenesis Across Species

Brown adipose tissue (BAT) is a thermogenic organ owing to its unique expression of uncoupling protein 1 (UCP1), which is a proton channel in the inner mitochondrial membrane used to dissipate the proton gradient and uncouple the electron transport chain to generate heat instead of adenosine triphosphate. The discovery of metabolically active BAT in human adults, especially in lean people after cold exposure, has provoked the “thermogenic anti-obesity” idea to battle weight gain. Because BAT can expend energy through UCP1-mediated thermogenesis, the molecular mechanisms regulating UCP1 expression have been extensively investigated at both transcriptional and posttranscriptional levels. Of note, the 3′-untranslated region (3′-UTR) of Ucp1 mRNA is differentially processed between mice and humans that quantitatively affects UCP1 synthesis and thermogenesis. Here, we summarize the regulatory mechanisms underlying UCP1 expression, report the number of poly(A) signals identified or predicted in Ucp1 genes across species, and discuss the potential and caution in targeting UCP1 for enhancing thermogenesis and metabolic fitness.

Stimulatory, but not anxiogenic, doses of caffeine act centrally to activate interscapular brown adipose tissue thermogenesis in anesthetized male rats

The role of central orexin in the sympathetic control of interscapular brown adipose tissue (iBAT) thermogenesis has been established in rodents. Stimulatory doses of caffeine activate orexin positive neurons in the lateral hypothalamus, a region of the brain implicated in stimulating BAT thermogenesis. This study tests the hypothesis that central administration of caffeine is sufficient to activate BAT. Low doses of caffeine administered either systemically (intravenous [IV]; 10 mg/kg) and centrally (intracerebroventricular [ICV]; 5–10 μg) increases BAT thermogenesis, in anaesthetised (1.5 g/kg urethane, IV) free breathing male rats. Cardiovascular function was monitored via an indwelling intra-arterial cannula and exhibited no response to the caffeine. Core temperature did not significantly differ after administration of caffeine via either route of administration. Caffeine administered both IV and ICV increased neuronal activity, as measured by c-Fos-immunoreactivity within subregions of the hypothalamic area, previously implicated in regulating BAT thermogenesis. Significantly, there appears to be no neural anxiety response to the low dose of caffeine as indicated by no change in activity in the basolateral amygdala. Having measured the physiological correlate of thermogenesis (heat production) we have not measured indirect molecular correlates of BAT activation. Nevertheless, our results demonstrate that caffeine, at stimulatory doses, acting via the central nervous system can increase thermogenesis, without adverse cardio-dynamic impact.