Brown to White Fat Transition Overlap With Skeletal Muscle During Development of Larger Mammals: Is it a Coincidence?

Abstract

In mammals, adipose tissues and skeletal muscles (SkMs) play a major role in the regulation of energy homeostasis. Recent studies point to a possibility of dynamic interplay between these 2 sites during development that has pathophysiological implications. Among adipose depots, brown adipose tissue (BAT) is the major energy-utilizing organ with several metabolic features that resemble SkM. Both organs are highly vascularized, innervated, and rich in mitochondria and participate in defining the whole-body metabolic rate. Interestingly, in large mammals BAT depots undergo a striking reduction and concomitant expansion of white adipose tissue (WAT) during postnatal development that shares temporal and molecular overlap with SkM maturation. The correlation between BAT to WAT transition and muscle development is not quite apparent in rodents, the predominantly used animal model. Therefore, the major aim of this article is to highlight this process in mammals with larger body size. The developmental interplay between muscle and BAT is closely intertwined with sexual dimorphism that is greatly influenced by hormones. Recent studies have pointed out that sympathetic inputs also determine the relative recruitment of either of the sites; however, the role of gender in this process has not been studied. Intriguingly, higher BAT content during early postnatal and pubertal periods positively correlates with attainment of better musculature, a key determinant of good health. Further insight into this topic will help in detailing the developmental overlap between the 2 seemingly unrelated tissues (BAT and SkM) and design strategies to target these sites to counter metabolic syndromes.

Keywords: adipose tissue; brown fat; larger mammals; myogenesis; perinatal development; skeletal muscle.

Figure 1.

Developmental maturation of muscle and brown fat. In larger mammals including human brown adipose tissue (BAT) is prominent only during perinatal stages. BAT quantity and its thermogenic capacity (ie, expression of UCP1, abundance of brown adipocytes, and mitochondrial density) sharply diminishes after birth. During the late postnatal period, the decline of BAT is reciprocally complemented by increased SkM oxidative capacity [25]. This might suggest the existence of a coordinated program that fine-tunes the metabolic functions of both sites. Further, it might be possible that SkM, after its maturation, takes over some of the metabolic functions of BAT in larger mammals. Interestingly, BAT makes a reappearance during puberty, where it closely correlates with the oxidative capacity of the SkM [26]. The oxidative capacity of SkM is highest during puberty and declines afterward. Starting from late adulthood, the appearance of ectopic fatty structures including white adipocytes in SkM gradually increases and is closely associated with metabolic disorders such as type 2 diabetes and its comorbidities [27, 28]. Created with biorender.com.

Figure 2.

The phylogenetic relatedness of 11 mammalian orders based on UCP-1 sequence similarity. Maximum likelihood analysis was used to define evolutionary similarity between UCP-1 proteins taken from 25 mammalian species from 11 orders. Animals of varied body sizes were selected from each order. The phylogeny was inferred using FastTree v.2.1 program with a GTR+ GAMMA model and 1000 bootstrap replicates. Midpoint rooting was used to establish the evolutionary tree. Each node represents bootstrap values, which are indicated with varying size of solid circles.

Figure 3.

Hypothetical expression of proteins associated with myogenesis and adipogenesis. (A) Expression of UCP-1 shows an interesting dichotomy between rodents and bovine/ovine species. While in rodents UCP-1 expression peaks after birth and stays high throughout life [76], in larger mammals its expression declines sharply after birth [41, 52]. UCP-1 expression is again upregulated for a short period during puberty and is correlated with muscle abundance and/or strength [77]. PGC1α and PPARγ are the major regulators of BAT functionality and follow a similar expression pattern in both rodent and bovine/ovine species. (B) Schematic showing postulated expression levels of transcription factors that mediate SkM differentiation and development in bovine/ovine species. The transcription factors that play a coordinated set of roles beginning at midgestation and continuing through the perinatal period are MRF-4, Myf-5, MyoD, and myogenin [78–80]. Interestingly, myogenin expression is upregulated last but is sustained until postpubertal life, playing a critical role in muscle maturation and hypertrophy [78, 79]. Created with biorender.com.

Figure 4.

Schematic representation showing synergistic interplay between muscle and brown fat development. During development, BAT and SkM share a common Myf5⁺ progenitor cell while WAT originates from Myf5⁻ progenitors. PRDM16 is a key transcriptional switch that induces commitment towards the BAT lineage, while inhibiting the SkM lineage [16, 105]. Thyroid hormone promotes metabolism and programs both sites to carry out adaptive thermogenesis. Thyroid hormone is a synergistic supplement alongside the SNS for enhancing UCP1 expression and structural modifications that are required for fully functional BAT in mice [112]. In an analogous manner, thyroid hormone also orchestrates the long-term adaptation of SkM, including the regulation of several key proteins like SERCA [113]. Moreover, BAT and SkM exhibit comparable regulation of oxidative metabolism through mitochondrial proteins, hormonal action, sympathetic innervations. [114]. All these features reflect that BAT is developmentally and functionally closer to SkM than WAT. Created with biorender.com.