Adipose tissue inflammation is a key factor leading to obesity-associated immune disorders, such as insulin resistance, beta cell loss in the pancreatic islets, meta-inflammation, and autoimmunity. Inhibiting adipose tissue inflammation is considered a straightforward approach to abrogate these diseases. However, recent findings show that certain pro-inflammatory cytokines are essential for the proper differentiation and functioning of adipocytes. Lipolysis is stimulated, and the thermogenic competence of adipocytes is unlocked by interleukin-6 (IL-6), a cytokine that was initially recognized as a key trigger of adipose tissue inflammation. Coherently, signal transducer and activator of transcription 3 (STAT3), which is a signal transducer for IL-6, is necessary for thermogenic adipocyte development. Given the impact of thermogenic adipocytes in increasing energy expenditure and reducing body adiposity, functions of IL-6 in the adipose tissue have gained attention recently. In this review, we show that IL-6 signaling may protect from excess fat accumulation by stimulating thermogenesis in adipocytes.

Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2′3′-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.

Prenatal adipose tissue development affects body composition and growth trajectory in early infancy, therefore it is a key determinant of adiposity in childhood. Childhood overweight and obesity increase the probability of being obese as an adult. After birth and in adulthood, adipose tissue macrophages (ATMs) are relevant constituents of the fat depots, and they are necessary for physiological adipose tissue development and fat metabolism. In obesity, however, ATMs may induce chronic inflammation leading to insulin resistance, pancreatic beta cell damage and self-immunity. Despite being relevant regulators of adipose tissue development and functioning, it is unknown whether ATMs are present in the fetal adipose tissue, therefore it is elusive whether they may affect the prenatal establishment of fat depots. Here we studied the distribution of ATMs in the human fetus between gestational weeks 17 and 38 and labeled ATMs in the early postnatal life. We found that CD45⁺/CD14⁺/CD68⁺ ATMs infiltrated the fetal adipose tissue from the 17th week of gestation and remained persistent throughout the second and third trimesters. ATMs were phagocytic in the neonate and expressed interleukin-6, along with other pro-inflammatory gene products. These findings show that ATMs colonize the adipose tissue early in gestation, raising the possibility that intrauterine ATM–adipocyte communication may exist, eventually allowing ATMs to affect prenatal adipose tissue development.

Catecholamines are crucial signaling molecules that initiate thermogenesis in adipocytes through beta-adrenergic receptors (ADRBs). Adipocyte catecholamine resistance is a common feature of pediatric obesity, often impeding weight loss and the maintenance of a healthy body fat percentage. Our aim was to identify possible mechanisms that may be responsible for the development of catecholamine resistance in adipocytes. We demonstrate that Lim homeobox 8 (LHX8), a transcription factor previously known for its role in gametogenesis, is essential for catecholamine-induced thermogenesis in human adipocytes. LHX8 is expressed in developing human adipocytes throughout intrauterine and perinatal life, as well as in adulthood, and its expression levels positively correlate with the expression of key thermogenesis genes. Pediatric obesity diminished adipocyte expression of LHX8. Functionally, ADRB stimulation failed to induce thermogenesis in both mouse and human adipocytes when LHX8 was absent. Conversely, LHX8 overexpression enhanced thermogenesis in murine adipocytes. Mechanistically, LHX8 stimulated adipocyte interleukin-33 (IL-33) synthesis in response to ADRB activation, which subsequently increased thermogenic gene expression in both human and mouse adipocytes. In conclusion, adipocyte LHX8 is indispensable for catecholamine-responsive thermogenesis and represents a promising novel therapeutic target to overcome catecholamine resistance and promote effective weight management.

Childhood obesity may be associated with an accelerated loss of thermogenic adipocytes, increasing the risk of progressive lipid accumulation and metabolic deterioration. Early detection of the loss of thermogenic adipocytes would allow improved intervention to abrogate childhood obesity, yet reliable markers of human thermogenic adipocytes remain limited. We previously identified expression of FAM153A (family with sequence similarity 153 member A) in the developing human adipose tissue. Here, we investigated the expression pattern and potential association of FAM153A with the thermogenic transcriptional program in the adipose tissue of infants, children, and adolescents. We found that adipocyte FAM153A expression was triggered by beta adrenergic receptor stimulation, a key signal of adipocyte thermogenesis. FAM153A protein was confined to preadipocyte and adipocyte nuclei, and FAM153A mRNA expression positively correlated with the mRNA levels of canonical thermogenic adipocyte markers including uncoupling protein 1 (UCP1), myogenic differentiation 1 (MYOD1), type II iodothyronine deiodinase (DIO2), transmembrane protein 26 (TMEM26), Lim Homeobox 8 (LHX8), beta adrenergic receptor 2 (ADRB2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). Importantly, FAM153A expression was positively associated not only with the expression of individual thermogenic genes but also with their coordinated co-expression. Collectively, our findings identify FAM153A as a novel mRNA biomarker of human thermogenic adipocytes that serves as a robust indicator of the thermogenic transcriptional network.