Keys to the switch of fat burning: stimuli that trigger the uncoupling protein 1 (UCP1) activation in adipose tissue

Abstract

As one of the main pathogenic factors of cardiovascular and cerebrovascular diseases, the incidence of metabolic diseases such as adiposity and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing annually. It is urgent and crucial to find more therapeutic targets to treat these diseases. Mainly expressed in brown adipocytes, mitochondrial uncoupling protein 1 (UCP1) is key to the thermogenesis of classical brown adipose tissue (BAT). Furthermore, white adipose tissue (WAT) is likely to express more UCP1 and subsequently acquire the ability to undergo thermogenesis under certain stimuli. Therefore, targeting and activating UCP1 to promote increased BAT thermogenesis and browning of WAT are helpful in treating metabolic diseases, such as adiposity and MASLD. In this case, the stimuli that activate UCP1 are emerging. Therefore, we summarize the thermogenic stimuli that have activated UCP1 in recent decades, among which cold exposure is one of the stimuli first discovered to activate BAT thermogenesis. As a convenient and efficient therapy with few side effects and good metabolic benefits, physical exercise can also activate the expression of UCP1 in adipose tissue. Notably, for the first time, we have summarized and demonstrated the stimuli of traditional Chinese medicines that can activate UCP1, such as acupuncture, Chinese herbal formulas, and Chinese medicinal herbs. Moreover, pharmacological agents, functional foods, food ingredients, and the gut microbiota are also commonly associated with regulating and activating UCP1. The identification and analysis of UCP1 stimuli can greatly facilitate our understanding of adipose tissue thermogenesis, including the browning of WAT. Thus, it is more conducive to further research and therapy for glucose and lipid metabolism disorders.

Keywords: Brown adipose tissue; Browning of white adipose tissue; The uncoupling protein 1; White adipose tissue.

Fig. 1

Overview of adipocyte structure, adipose tissue distribution, and stimuli that activate UCP1. A: The distribution and fat mass of WAT and BAT in the obese human body. B: Stimuli that stimulate WAT browning. C: The distribution and fat mass of WAT and BAT in the healthy body. WAT is primarily categorized into visceral WAT and subcutaneous WAT. WAT is distributed primarily among key organs and blood vessels in the abdominal cavity as well as under the skin [4]. In contrast, BAT constitutes a small portion of all adult human fat tissue and can be found in the mediastinal, supraclavicular, abdominal, cervical, axillary, and paraspinal regions [5]. D: Characteristics of different fat cells. Abundant mitochondria, multilocular lipid droplets, and abundant UCP1 characterize brown adipocytes. The morphological and structural characteristics of white adipocytes are opposite those of brown adipocytes. Brite adipocytes have similar morphologies and functions as brown adipocytes

Fig. 2

The partial mechanisms by which cold exposure activates UCP1. Upon exposure to cold temperatures, both animals and humans trigger the activation of the sympathetic nervous system (SNS). This leads to the release of catecholamines (CAs) from the sympathetic nerves that innervate BAT, consequently initiating the activation of β-adrenergic receptors (β-AR) and subsequent downstream signaling pathways, such as the PKA/p-AIDA pathway, ultimately activating UCP1 activity

Fig. 3

The partial mechanisms by which physical exercise upregulates and activates UCP1. First, physical exercise can facilitate the upregulation of critical genes in POMC neurons, including β-endorphin (β-END) and the mitochondrial frame of the 12 S RNA-c (MOTS-c). This cascade subsequently facilitates the activation of UCP1 in adipose tissue (the yellow line). Second, engaging in physical activity results in an increase in PGC-1α within skeletal muscle. This upregulation subsequently triggers the expression of the fibronectin type III domain-containing protein 5 (FNDC5) gene, which is responsible for encoding irisin, a myokine involved in various physiological processes. Furthermore, irisin substantially affects adipose tissue by upregulating UCP1 expression (green line). Third, exercise facilitates the activation of the sympathetic nervous system (SNS) and the release of CA from the SNS, which mediates the upregulation of UCP1 (black line)

Fig. 4

Acupoints are stimuli that can promote UCP1 expression in adipose tissue. TCM defines meridians as channels that run the whole body’s qi and blood and communicate with the entire body’s viscera and joints. When pathological changes take place in the viscera, they may be transmitted to the body’s surface through the meridian system. Similarly, we can cure diseases inside the body by stimulating acupoints, such as through acupuncture, acupoint embedding (ACE), and auricular acupuncture (AA). A. Shenshu (BL23), Pishu (BL20), and Ganshu (BL18) are in the gallbladder meridian; B. Zusanli (ST36), Fenglong (ST40), Tianshu (ST25), and Neiting (ST44) are in the stomach meridian, and Guanyuan (CV4) and Zhongwan (CV12) are in the conception vessel; C. Auricular stimulation sites of the stomach and small intestine.

Fig. 5

The formula regulates the thermogenesis gene UCP1 to achieve a balance of BAT and WAT in humans. Yin and Yang summarize the attributes or two opposite aspects of interrelated things or phenomena in nature. On the basis of the properties and functions of WAT and BAT, we speculate that WAT stores energy and belongs to Yin; BAT consumes energy and produces heat, which is Yang. When the human body is in a state of adiposity, i.e., when the WAT increases, the BAT decreases, which results in dysfunction of the human fat tissue and an imbalance of Yin and Yang. The formula can increase the expression level of UCP1, thereby increasing the heat production and energy consumption of fat tissue and restoring the normal function of fat tissue and the balance of Yin and Yang in the body

Fig. 6

Chinese medicinal herbs and their bioactive compounds are stimuli that can activate UCP1. The Ginseng Radix et Rhizoma and ginsenosides, the Coptidis Rhizoma and berberine, the Zingberis Rhizoma Recens and Zingerone and 6-Gingerol, the Glycyrrhizae Radix et Rhizoma and licochalcone A, the Cinnamomi Cortex and cinnamaldehyde, the Menthae Haplocalycis Herba and menthol, all demonstrate the capacity to activate UCP1 in adipose tissue

Fig. 7

Food ingredients that can activate UCP1. Resveratrol, anthocyanins, fucoxanthin, tea catechins, and capsaicin in many foods, such as fruits and vegetables, can activate UCP1 in adipose tissue

Fig. 8

The microbiota regulates the abundance of UCP1 in adipose tissue through microbiota metabolites, such as bible acids and succinate