Brown adipocyte and browning thermogenesis: metabolic crosstalk beyond mitochondrial limits and physiological impacts

Abstract

Brown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and browning process are capable of thermogenesis, the uncoupling metabolism which allows them to promote balanced energy expenditure, a fundamental mechanism for improving metabolic disorders. Thermogenesis process is not only performed by the thermogenin UCPs within the mitochondria, but instead, is globally regulated within brown and browning adipose tissues, which induces signalling molecules that can be sent to nearby and distant tissues to generate systemic effects on metabolism. This review highlights thermogenesis and describes the crosstalk between different organelles within browning and brown adipocytes, as well as their interorgan axes to regulate whole body metabolism. Finally, browning and thermogenesis activation will also be discussed in terms of physiological conditions, in which, we propose that thermogenesis and functional activities of brown adipocytes should be considered individually in future clinical application.

Keywords: Thermogenesis; diabetes; glucose tolerance; obesity; triglyceride.

Figure 1.

Browning and thermogenesis activation. Acclimatization to cold-temperatures may trigger the sympathetic nervous system, resulting in norepinephrine secretion and subsequently activating thermogenesis in brown adipocytes through β-adrenergic receptors. In addition to norepinephrine, β-adrenergic receptor agonists such as CL-316,243 activate protein kinase a (PKA) and increase cAMP levels, leading to the acceleration of TGR breakdown and FFA production, a crucial substrate for the regulation of mitochondria and UCP-1. Thyroid hormone (TH) binds to TR on BAT to activate SIRT pathway via deacetylation of the downstream molecule FOXO1, resulting in adipogenesis of BAT. Leptin correlated with hypothalamic regulation to increase gene expression of Pgc-1a, Cidea and Ucp1 in BAT and improves energy expenditure in the body. Estrogen receptors are activated by oestradiol in the ventromedial hypothalamus to enhance sympathetic nervous system regulation via AMPK to upregulate Ucp1, Pgc1a and Pgc1b in BAT, which activate BAT thermogenesis. Activated brown adipocytes have enhanced lipolysis and triglyceride-FFA cycling, resulting in a reduction in accumulated triglycerides in the bloodstream and nearby organs and an increase in mitochondrial activity. Contact between small lipid droplets and mitochondria is required for thermogenic activity to occur. Furthermore, higher mitochondrial activity contributes to an increase in the expression of UCP1, a brown adipocyte-specific marker that plays an important role in energy-heat conversion in BAT. In addition, cold-temperature acclimation also leads to higher levels of leptin and thyroid hormones, leading to an increase in insulin sensitivity, thus boosting glucose transporter activity and subsequently decreasing glucose levels in the bloodstream. Conversely, exercise activates the secretion of Fndc5 from myocytes. Inside adipocytes, Fndc5 is cleaved to form the peptide irisin, which activates PPARγ to regulate the browning process.

Figure 2.

Thermogenic activation forms a signal transduction network to generate systemic effects. Thermogenic mechanisms in brown adipocytes and signal transduction to distant tissues. 1. Long-chain FAs are transported from the WAT to the liver, where they are converted to acylcarnitine (AC). AC is preferably used by BAT to fuel thermogenesis in the mitochondria. UCP-1 in the mitochondria dissipates protons into heat instead of producing ATP. 2. Lipoprotein lipase (LPL) supports the transport of TG and FA across the blood stream into BAT. 3. in turn, lipolytic products from the mitochondria further regulate the activity of LPL to enhance membrane permeability and the import of substances into BAT. 4. Cardiolipins (CLs) are synthesized and exported from the mitochondria to the ER to support communication with the nucleus via the stress response and Nrf1, which results in the regulation of thermogenic and transporter genes such as UCP1, CD36, and glucose transporters. 5. the involvement of lysosomes occurs via the activity of lysosomal acid lipase (LAL), which regulates UCP1 expression and mitophagy and remodels BAT morphology and function. 6. the endoplasmic reticulum (ER) protein Calsyntenin 3β binds to S100 proteins and mediates their secretion as a neurotrophic factor to recruit innervation. 7. Activated BAs produce a secretome in the blood stream to regulate distance to support their maintenance and enhance systemic metabolism.