The Role of Brown Adipose Tissue and Energy Metabolism in Mammalian Thermoregulation during the Perinatal Period

Abstract

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.

Keywords: altricial; brown adipose tissue; hypothermia; mammals; neonate; precocial; thermostability.

Figure 1

Characteristics and activation of the brown adipose tissue in mammals. When mammals are exposed to cold environments, it activates the sympathetic nervous system and the consequent release of catecholamines, notably NE from the adrenal glands. NE binds to β3-AR located in BAT to start a series of biochemical reactions to produce heat. cAMP production by AC results in the activation of the PKA, a protein that promotes lipolysis and thermogenesis through CREB, P38, and ATF2. Thyroid hormones (T4 and T3) also participate in gene expression and TG uptake, as well as GR and glucose. The conversion of TG to FA is used by the mitochondria to produce heat. In the mitochondria’s membrane, UCP1 receptors and cytochrome c participate in thermogenesis following β-oxidation, the TCA cycle, and the electron transport chain mechanism for thermogenesis. (A) Schematic deposit of BAT; AC: adenylyl cyclase; ATF2: activating transcription factor 2. (B) Mitochondria close-up; β3-AR: beta3-adrenergic receptor. (C) Mitochondrial membrane; cAMP: cyclic AMP; CREB: cAMP response element-binding protein; GR: glucocorticoid; FA: fatty acids; NE: norepinephrine; PKA: protein kinase A; T3/T4: thyroid hormone; TG: triglyceride; UCP1: uncoupling protein 1.

Figure 2

Non-shivering thermogenesis in neonate mammals. The activation of BAT to produce heat starts with the recognition of an environmental or core temperature drop by cold-sensitive neurons. The signals are transmitted to the DRG and the DMH in the POA by the LPBel pathway. From the DMH, a region where GABAergic neurons participate, projection to the rRPA reaches the IML region of the spinal cord. From this region, sympathetic afferents are directly connected to the BAT, where the release of NE activates the β3-AR thanks to the high vascularization present in BAT (through the thoracodorsal artery and the median perforating interscapular vein). The binding of NE to the β3-AR promotes lipogenesis, glycolysis, and the production of TG and FA as a fuel to the mitochondria to produce heat and increase core temperature. 5-HT: serotonin; AC: adenylyl cyclase; β3-AR: beta3-adrenergic receptor; cAMP: cyclic AMP; DMH: dorsomedial hypothalamus; DRG: dorsal root ganglion; FA: fatty acids; Glu: glutamate; IML: intermediolateral; LPBel: external lateral region of the lateral parabrachial nucleus; NE: norepinephrine; PKA: protein kinase A; POA: preoptic area; rRPA: rostral raphe pallidus; TG: triglyceride; UCP1: uncoupling protein 1.

Figure 3

Neural circuit of shivering thermogenesis. When exposed to cold stress, peripheral thermosensitive afferents (known as cold-sensitive neurons) TRPA1 and TRPM8 detect noxious cold. The stimulus is transduced into an electric signal to ascend through the DRG and DH to the hypothalamus POA using the LPBel. In this pathway, glutamatergic neurons have an excitatory role in the premotor shiver nucleus located in the rRPA. Subsequently, these fibers stimulate the VH and α and γ motoneurons that innervate the skeletal muscle and, when excited, contract striated muscle fibers. The afferent input reaches type Ia and II fibers that enhance muscle fiber action potential to produce shivering and, consequently, the heat production. DA: dorsal hypothalamic area; DH: dorsal horn; DMH: dorsomedial hypothalamus; DRG: dorsal root ganglion; Glu: glutamate; LPBel: external lateral part of the lateral parabrachial nucleus; POA: preoptic area; rRPA: rostral raphe pallidus; TRPA: transient receptor potential ankyrin 1; TRPM8: transient receptor potential melastatin 8; VH: ventral horn.

Figure 4

Radiometric images showing temperature differences in areas with brown adipose tissue of altricial neonates. (A) Chihuahua puppy. In dogs, BAT pads are in the interscapular, perirenal, and pericardial regions. Evaluating the surface temperature of BAT (spot) shows an average value of 34.4 °C. (B). Wistar rat pup. When comparing the average temperature of the interscapular BAT (El1) of the rat pup (33.6 °C) with the puppies, there is a difference of 0.8 °C. This difference can be attributed to the difference in size and the presence of hair at birth in dogs, whereas rat pups are born hairless and their body surface area is larger than their overall size, losing a greater proportion of heat. Maximal temperature is indicated with a red triangle and the minimal with a blue triangle. Radiometric images were obtained using a T1020 FLIR thermal camera. Image resolution 1024 × 768; up to 3.1 MP with UltraMax. FLIR Systems, Inc. Wilsonville, OR, USA.

Figure 5

Temperature comparison of the interscapular region between species with and without BAT at birth. (A) Large White X Landrace newborn piglet. The maximum, minimum, and average temperature of the piglet at the interscapular region (El1) shows values of 33.3 °C, 29.9 °C, and 32.2 °C. (B) Wistar rat pups. The BAT temperature (El1) registered increases in the temperature of the pup when compared to the piglet’s information. The average temperature increased by 1.4 °C, whereas increases of 4.4 °C and 2.1 °C were recorded for the minimum and average temperatures. The differences in surface temperature between both species can be attributed to traits in each animal. Although pigs, a semi-altricial species, are born with sparsely distributed hair and are bigger than rat pups, they are born without BAT reserves, making them susceptible to hypothermia. In contrast, although rat pups are born hairless, they have interscapular BAT reserves that produce heat when exposed to cold stress and rely on behavioral modifications such as huddling to preserve heat. Maximal temperature is indicated with a red triangle and the minimal with a blue triangle. Radiometric images were obtained using a T1020 FLIR thermal camera. Image resolution 1024 × 768; up to 3.1 MP with UltraMax. FLIR Systems, Inc. Wilsonville, OR, USA.

Figure 6

Influence of hair and post-natal days on the newborn rat pup. (A,C,E) thermograms show hairless 1-day-old rat pups, whereas (B,D,F) show 1-week-old rat pups with hair. (A,B) When comparing the maximum temperature between a hairless ((A), El1) and a 1-week-old rat pup ((B), El1), the temperature of the pup with hair is 0.4 °C higher. (C,D) The maximum temperature of the nest of newborn rat pups ((C), El1) is 36.9 °C, whereas that of the pups with hair ((D), El1) is 37.5 °C, 0.6 °C higher. (E,F) Regarding the position of the neonate in the nest, it can be observed that 1-day-old pups stay inside the nest, next to their littermates, with a maximum BAT temperature ((E), El1) of 36.3 °C. In contrast, the BAT temperature ((F), El1) of the pup with hair is 1.9 °C lower than the (E) pup. In general, it can be observed that 1-week-old rat pups have thermoregulatory benefits due to the presence of hair and the increase in size, which make them auto-sufficient to thermoregulate and not dependent on nesting to maintain their body core temperature. The decrease in BAT temperature of older animals could also be explained by a higher thermoregulatory challenge in hairless neonates, where BAT requires more activation to produce heat. Maximal temperature is indicated with a red triangle and the minimal with a blue triangle. Radiometric images were obtained using a T1020 FLIR thermal camera. Image resolution 1024 × 768; up to 3.1 MP with UltraMax. FLIR Systems, Inc. Wilsonville, OR, USA.

Figure 7

Importance of the position of the newborn in the nest for thermoregulation in 1-day-old Wistar rat pups. (A) Rat pups alone. The temperature of the interscapular BAT (El1) shows maximum, minimum, and average values of 35.9 °C, 34.8 °C, and 35.4 °C, respectively. When evaluating the proximal temperature of the nest (El2) around the pup, 26.0 °C is the minimum value recorded, the same as in the distal zone of the nest (El3). (B) Rat pups grouped in a line. The BAT temperature (El1) of one of the pups in this position has a maximum value of 37.0°, 1.1 °C higher than that of the rat pup alone. The temperature increases were also observed for the minimum and average values, being 0.8 °C and 1 °C higher, respectively, than the A pup. When comparing the minimum temperature of the proximal nest, a rise in temperature of 1.2 °C can also be observed (C). Rat pups huddling in a circle. This position promotes a maximum BAT temperature of 37.3 °C, 1.4 °C higher than that of the pup standing alone. Similarly, the minimal and average values of the proximal nest, when compared to the pup alone, are 1.5 °C and 4 °C higher, respectively. The high values observed in the pups formed in a circle are due to the importance of huddling, the most important behavioral adaptation of newborn rodents to prevent heat losses by maintaining contact with their conspecifics.