Thermogenesis and Energy Metabolism in Brown Adipose Tissue in Animals Experiencing Cold Stress

Abstract

Cold exposure is a regulatory biological functions in animals. The interaction of thermogenesis and energy metabolism in brown adipose tissue (BAT) is important for metabolic regulation in cold stress. Brown adipocytes (BAs) produce uncoupling protein 1 (UCP1) in mitochondria, activating non-shivering thermogenesis (NST) by uncoupling fuel combustion from ATP production in response to cold stimuli. To elucidate the mechanisms underlying thermogenesis and energy metabolism in BAT under cold stress, we explored how cold exposure triggers the activation of BAT thermogenesis and regulates overall energy metabolism. First, we briefly outline the precursor composition and function of BA. Second, we explore the roles of the cAMP- protein kinase A (PKA) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways in thermogenesis and energy metabolism in BA during cold stress. Then, we analyze the mechanism by which BA regulates mitochondria homeostasis and energy balance during cold stress. This research reveals potential therapeutic targets, such as PKA, AMPK, UCP1 and PGC-1α, which can be used to develop innovative strategies for treating metabolic diseases. Furthermore, it provides theoretical support for optimizing cold stress response strategies, including the pharmacological activation of BAT and the genetic modulation of thermogenic pathways, to improve energy homeostasis in livestock.

Keywords: brown adipose tissue; cold stress; energy metabolism and balance; mitochondria homeostasis; non-shivering thermogenesis.

Figure 1

cAMP-PKA signaling pathway in brown adipocyte thermogenesis. Cold stimuli are transmitted to the hypothalamus through the skin, indirectly releasing norepinephrine (NE) to activate the cAMP-protein kinase A (PKA) signaling pathway via the β3-adrenergic receptor (β3-AR). PKA phosphorylation activates factors upstream of the activation of the peroxisome-proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the nucleus and induces the expression of PGC-1α. This activates intranuclear uncoupling protein (UCP1) and acts on mitochondria for thermogenesis. The PKA-dependent activation of p38 mitogen-activated protein kinase (MAPK) activates intranuclear PGC-1α, which induces the expression of UCP1 and promotes thermogenesis in BA. PKA promotes lipolysis within lipid droplets, increases the release of free fatty acids (FFAs), and utilizes UCP1 in mitochondria to regulate BA thermogenesis. Adenylate cyclase (AC), cAMP response-origin binding protein (CREB), peroxisome-proliferator-activated receptor γ (PPARγ), lysine-specific demethylase1 (LSD1), positive regulatory domain-containing protein (PRDM16), MAP kinase kinase (MKK3), zinc finger protein (Zfp516), transcription factor 2 (ATF2), hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and unesterified fatty acids (FA).

Figure 2

AMPK signaling pathway in brown adipocyte thermogenesis. Cold stimuli are delivered to the hypothalamus through the skin and activate the AMP-activated protein kinase (AMPK) signaling pathway directly via BA surface adrenergic receptor α1A (ADRA1A) or indirectly by releasing norepinephrine (NE), which activates the signal AMPK pathway via the adrenergic receptor (β3-AR). AMPK activation by upstream multimers (Liver kinase B1 LKB1, Mouse protein-25 MO25, STRAD) induces the phosphorylation of peroxisome-proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the nucleus, increasing UCP1 transcription and promoting thermogenesis. Upregulating AMPK directly activates intracellular PGC-1α, which induces UCP1 expression and enhances thermogenesis. AMPK activates nuclear respiratory factor 1 (Nrf-1) by inducing PGC-1α transcription, upregulates mitochondrial transcription factor A (TFAM) expression, and increases mitochondrial DNA transcription and replication. Glucose transporter 4 (GLUT4).

Figure 3

Mitochondrial biology and mitophagy coordinate organismal energy homeostasis [104,121]. (1) Healthy BA mitochondrial homeostasis and maintaining energy balance. (2) Aged/damaged mitochondria, unable to maintain mitochondrial homeostasis, result in defective thermogenesis and energy homeostasis. Mitophagy is greater than mitochondrial biogenesis, and mitophagy is excessive/damaged mitochondrial biogenesis. (3) Mitochondrial biogenesis is greater than mitophagy, and mitochondrial biogenesis is excessive/damaged mitophagy.

Figure 3

Mitochondrial biology and mitophagy coordinate organismal energy homeostasis [104,121]. (1) Healthy BA mitochondrial homeostasis and maintaining energy balance. (2) Aged/damaged mitochondria, unable to maintain mitochondrial homeostasis, result in defective thermogenesis and energy homeostasis. Mitophagy is greater than mitochondrial biogenesis, and mitophagy is excessive/damaged mitochondrial biogenesis. (3) Mitochondrial biogenesis is greater than mitophagy, and mitochondrial biogenesis is excessive/damaged mitophagy.

Figure 4

AMPK mediates brown adipocyte thermogenesis and energy regulation [74,151]. A: Hypothalamic AMPK-SNS-BAT axis. BAT is activated by inhibiting hypothalamic AMPK, and SNS transmits signals from AMPK inactivation to BAT to upregulate lipolysis and promote thermogenesis and energy regulation. B: BA-AMPK axis. Norepinephrine (NE) released via the SNS binds to the β3-adrenergic receptor (β3-AR), activating cAMP-PKA and AMPK, which ultimately increases lipolysis and thermogenesis. AMPK also regulates energy homeostasis via mitochondrial biogenesis and mitophagy homeostasis. The activation of AMPK leads to an increase in the uptake of triglyceride (TG)-derived nonesterified fatty acids (NEFA) from lipoproteins and inhibits carnitine palmitoyl transferase 1 (CPT1) in mitochondria, enhances FA transport to mitochondria, and promotes lipolysis for thermogenesis. Estradiol (E2), triiodothyronine (T3), leptin (Lep), an unc-51-like autophagy kinase 1 (ULK1).