Fig 5 - uploaded by Jan Nedergaard
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The basic principles for heat production in brown adipose tissue. The brown-fat cells are stimulated by norepinephrine (NE) released from the sympathetic nervous system. The norepinephrine binds, as indicated, to its receptor in the plasma membrane, and through intracellular signalling processes, this leads to degradation of the triglycerides (TG) in the lipid droplets, and the released free fatty acids (FFA) interact with uncoupling protein-1 (UCP1) and, through this, overcome the inhibition of UCP1 caused by cytosolic purine nucleotides such as ATP (and ADP, GTP and GDP). This leads to respiration in the mitochondria that is uncoupled from ATP synthesis. All energy from the combustion of substrate (food) is therefore directly released as heat.
Source publication
Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and asse...
Citations
... In cardiovascular protection, the anti-atherogenic, anti-inflammatory effect on the vascular wall and inhibition of macrophage activation play a significant role [18,41]. Animal models have shown that GLP-1 can increase energy expenditure and regulate heat production and conversion from white adipose tissue to brown adipose tissue in obese mice [42], although human data on this effect are not yet convincing [18,43]. The weight-reducing effect achieved with GLP-1 receptor agonists may alleviate cardiac insulin resistance in obese and overweight individuals. ...
Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are already available to treat obesity, which can help reduce appetite and/or reduce caloric intake. Incretin-based peptides exert their effect through G-protein-coupled receptors, the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and glucagon peptide hormones are important regulators of insulin secretion and energy metabolism. Understanding the role of intercellular signaling pathways and inflammatory processes is essential for the development of effective pharmacological agents in obesity. GLP-1 receptor agonists have been successfully used, but it is assumed that their effectiveness may be limited by desensitization and downregulation of the target receptor. A growing number of new agents acting on incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may show further significant therapeutic potential. This narrative review summarizes the therapeutic effects of different incretin hormones and presents future prospects in the treatment of T2DM and obesity.
... 3.9. LDT409 increases energy expenditure at thermoneutrality Mice housed at room temperature (21e23 C) undergo adaptive thermogenesis to maintain their core body temperature [72,73]. Therefore, to examine the effect of LDT409 on thermogenesis, HFD-fed mice were housed at thermoneutral condition (30 C), where adaptive thermogenesis is minimally active. ...
... Another indirect mechanism of UCP-1 activation is induced by AMPK activation, favoring thermogenic BAT function by the production of free FAs or SIRT1 activation [82,84,85]. It is important to keep in mind that one of the classical mechanisms of BAT activation is mediated by β-AR, activating UCP-1 directly as targets of the CNS for fat burning or indirectly through cyclic AMP (cAMP), resulting in FA generation [86,87]. In humans, β2-AR is the predominant receptor for BAT lipolysis. ...
Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.
... Brown adipose tis s ue (BAT) is o ften co nsidered to be t he pr incip a l site of NST in placental m amm al s. Thi s ti s s ue is densely p acke d wi th mi t oc h on dri a w ithin which oxidati ve p hosp ho rylatio n beco m es un coupled from ATP synthesis in th e presen ce of uncoupling protein 1 (UCP1), producing heat as a by-product ( Ne dergaard et a l. 2001 ; Cann on an d Nedergaard 2011 ). Alt hough t hi s mech ani sm of NST i s commo nly u p regulated d uring cold acclimatio n in placental m amm al s, oth er en doth erms, in c luding mar su p ials, m on otrem es, an d birds, lac k BAT ( Nowac k et al . ...
Synopsis
Homeothermic endotherms defend their body temperature in cold environments using a number of behavioral and physiological mechanisms. Maintaining a stable body temperature primarily requires heat production through shivering or non-shivering thermogenesis (NST). Although the use of NST is well established in mammalian systems, the mechanisms and extent to which NST is used in birds are poorly understood. In mammals, one well-characterized mechanism of NST is through uncoupling of Ca2+ transport from ATP hydrolysis by sarco/endoplasmic reticulum ATPase (SERCA) in the skeletal muscle, which generates heat and may contribute to Ca2+ signaling for fatigue resistance and mitochondrial biogenesis. Two small proteins—sarcolipin (SLN) and phospholamban (PLN)—are known to regulate SERCA in mammals, but recent work shows inconsistent responses of SLN to cold acclimation in birds. In this study, we measured SERCA uncoupling in the pectoralis flight muscle of control (18°C) and cold-acclimated (−8°C) dark-eyed juncos (Junco hyemalis) that exhibited suppressed SLN transcription in the cold. We measured SERCA activity and Ca2+ uptake rates for the first time in cold-acclimated birds and found greater SERCA uncoupling in the muscle of juncos in the cold. However, SERCA uncoupling was not related to SLN or PLN transcription or measures of mitochondrial biogenesis. Nonetheless, SERCA uncoupling reduced an individual’s risk of hypothermia in the cold. Therefore, while SERCA uncoupling in the cold could be indicative of NST, it does not appear to be mediated by known regulatory proteins in these birds. These results prompt interesting questions about the significance of SLN and PLN in birds and the role of SERCA uncoupling in response to environmental conditions.
... Thermogenesis is also an important process that can impact animal weight as it is essential for maintaining body temperature and basal metabolism (Hhmms-Hagen, 1989;Cannon and Nedergaard, 2011). Considering that thermogenesis is linked to energy expenditure, it is plausible that it may also influence the ADG of animals, and consequently body weight at specific time points (e.g., YW). ...
Introduction: Nellore cattle (Bos taurus indicus) is the main beef cattle breed raised in Brazil. This breed is well adapted to tropical conditions and, more recently, has experienced intensive genetic selection for multiple performance traits. Over the past 43 years, an experimental breeding program has been developed in the Institute of Animal Science (IZ, Sertaozinho, SP, Brazil), which resulted in three differentially-selected lines known as Nellore Control (NeC), Nellore Selection (NeS), and Nellore Traditional (NeT). The primary goal of this selection experiment was to determine the response to selection for yearling weight (YW) and residual feed intake (RFI) on Nellore cattle. The main objectives of this study were to: 1) identify copy number variation (CNVs) in Nellore cattle from three selection lines; 2) identify and characterize CNV regions (CNVR) on these three lines; and 3) perform functional enrichment analyses of the CNVR identified.
Results: A total of 14,914 unique CNVs and 1,884 CNVRs were identified when considering all lines as a single population. The CNVRs were non-uniformly distributed across the chromosomes of the three selection lines included in the study. The NeT line had the highest number of CNVRs (n = 1,493), followed by the NeS (n = 823) and NeC (n = 482) lines. The CNVRs covered 23,449,890 bp (0.94%), 40,175,556 bp (1.61%), and 63,212,273 bp (2.54%) of the genome of the NeC, NeS, and NeT lines, respectively. Two CNVRs were commonly identified between the three lines, and six, two, and four exclusive regions were identified for NeC, NeS, and NeT, respectively. All the exclusive regions overlap with important genes, such as SMARCD3, SLC15A1, and MAPK1. Key biological processes associated with the candidate genes were identified, including pathways related to growth and metabolism.
Conclusion: This study revealed large variability in CNVs and CNVRs across three Nellore lines differentially selected for YW and RFI. Gene annotation and gene ontology analyses of the exclusive CNVRs to each line revealed specific genes and biological processes involved in the expression of growth and feed efficiency traits. These findings contribute to the understanding of the genetic mechanisms underlying the phenotypic differences among the three Nellore selection lines.
... Ambient temperature poses a mild cold stress to the animals that results in sympathetic activation to maintain their body temperature, whereas under thermoneutrality (30°C) the sympathetic nervous system is minimally activated (54)(55)(56). To further investigate whether the leaner phenotype in AGKO mice is dependent on sympathetic activation, we also conducted HFD challenge in AGKO and f/f mice under thermoneutrality (30°C). ...
The stomach-derived orexigenic hormone ghrelin is a key regulator of energy homeostasis and metabolism in humans. The ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR), is widely expressed in the brain and gastrointestinal vagal sensory neurons, and neuronal GHSR knockout results in a profoundly beneficial metabolic profile and protects against diet-induced obesity (DIO) and insulin resistance. Here we show that in addition to the well characterized vagal GHSR, GHSR is robustly expressed in gastrointestinal sensory neurons emanating from spinal dorsal root ganglia. Remarkably, sensory neuron GHSR deletion attenuates DIO through increased energy expenditure and sympathetic outflow to adipose tissue independent of food intake. In addition, neuronal viral tract tracing reveals prominent crosstalk between gut non-vagal sensory afferents and adipose sympathetic outflow. Hence, these findings demonstrate a novel gut sensory ghrelin signaling pathway critical for maintaining energy homeostasis.
... Figure S2). Taken together, these findings point to a significant contribution of thermogenesis to energy expenditure in mice housed at ambient temperature, as previously reported [26][27][28]. ...
Objective
Impaired adipogenic differentiation exacerbates metabolic disease in obesity. This study reported that high‐fat diet (HFD)‐fed mice housed at thermoneutrality exhibited impaired adipogenic differentiation, attributed to increased expression of histone deacetylase 9 (HDAC9). However, the impact of HFD on adipogenic differentiation is reportedly variable, possibly reflecting divergent environmental conditions such as housing temperature.
Methods
C57BL/6J (wild‐type [WT]) mice were housed at either thermoneutral (28–30°C) or ambient (20–22°C) temperature and fed HFD or chow diet (CD) for 12 weeks. For acute exposure experiments, WT or transient receptor potential cation channel subfamily M member 8 (TRPM8) knockout mice housed under thermoneutrality were acutely exposed to ambient temperature for 6 to 24 h.
Results
WT mice fed HFD and housed at thermoneutrality, compared with ambient temperature, gained more weight despite reduced food intake. They likewise exhibited increased inguinal adipose tissue HDAC9 expression and reduced adipogenic differentiation in vitro and in vivo compared with CD‐fed mice. Conversely, HFD‐fed mice housed at ambient temperature exhibited minimal change in adipose HDAC9 expression or adipogenic differentiation. Acute exposure of WT mice to ambient temperature reduced adipose HDAC9 expression independent of sympathetic β‐adrenergic signaling via a TRPM8‐dependent mechanism.
Conclusions
Adipose HDAC9 expression is temperature sensitive, regulating adipogenic differentiation in HFD‐fed mice housed under thermoneutrality.
... In mice, thermoneutrality is ca. 30°C (Cannon & Nedergaard, 2011), but humans are thermoneutral at much lower temperatures and, therefore, humans only display limited thermogenic activity (de Jong et al, 2019). However, in colder regions, people display marked NST (van Marken Lichtenbelt et al, 2009), indicating that the environmental temperature are major determinant of BAT activity. ...
Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.
... The mice with whitened brown adipose tissue are also reported to present with lower metabolism (energy expenditure) [44,45], but this is generally expressed-physiologically erroneously-per body weight, a calculation process that automatically makes obese mice demonstrate low metabolic rate (as has been discussed elsewhere, e.g. [46][47][48][49]). All these observations can be summarized to imply a decreased capacity for (adrenergically induced) non-shivering/diet-induced thermogenesis, but to our knowledge this has not been experimentally verified. ...
The issue under discussion here is whether a decrease in the degree of UCP1 activity (and brown adipose tissue activity in general) could be a cause of obesity in humans. This possibility principally requires the existence of the phenomenon of diet-induced thermogenesis. Obesity could be a consequence of a reduced functionality of diet-induced thermogenesis. Experiments in mice indicate that diet-induced thermogenesis exists and is dependent on the presence of UCP1 and thus of brown adipose tissue activity. Accordingly, many (but not all) experiments indicate that in the absence of UCP1, mice become obese. Whether similar mechanisms exist in humans is still unknown. A series of studies have indicated a correlation between obesity and low brown adipose tissue activity, but it may be so that the obesity itself may influence the estimates of brown adipose tissue activity (generally glucose uptake), partly explaining the relationship. Estimates of brown adipose tissue catabolizing activity would seem to indicate that it may possess a capacity sufficient to help maintain body weight, and obesity would thus be aggravated in its absence.
This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part II)’.
... The heat produced through this mechanism and fatty acid oxidation [65][66][67] is dispersed around the body through the bloodstream, ensuring that the core temperature is maintained within a narrow range after exposure to cold [67][68][69][70][71]. ...
Hypothermia is one of the most common causes of mortality in neonates, and it could be developed after birth because the uterus temperature is more elevated than the extrauterine temperature. Neonates use diverse mechanisms to thermoregulate, such as shivering and non-shivering thermogenesis. These strategies can be more efficient in some species, but not in others, i.e., altricials, which have the greatest difficulty with achieving thermoneutrality. In addition, there are anatomical and neurological differences in mammals, which may present different distributions and amounts of brown fat. This article aims to discuss the neuromodulation mechanisms of thermoregulation and the importance of brown fat in the thermogenesis of newborn mammals, emphasizing the analysis of the biochemical, physiological, and genetic factors that determine the distribution, amount, and efficiency of this energy resource in newborns of different species. It has been concluded that is vital to understand and minimize hypothermia causes in newborns, which is one of the main causes of mortality in neonates. This would be beneficial for both animals and producers.
