Leptin, more than satiety; examining the relationship between adipose‐secreted leptin and muscle form and function

Healthy adipose tissue is a major producer of cytokines (referred to as 'adipokines') that signal to nearly every bodily system and organ, and adipokine dysregulation is strongly implicated in metabolic syndrome. Most notable for its role as a satiety signal, adipose-secreted leptin is becoming recognized for its wide-spanning systemic metabolic effects as leptin has been shown to regulate glucose and lipid metabolism independent of feeding behaviour (Muoio & Dohm, 2002). One particular area of interest is understanding the effects of adipose-secreted leptin on skeletal muscle health. To examine the effects of leptin on skeletal muscle, the paper by Collins et al. (2022) utilized a lipodystrophy mouse model that lacks the presence of typical adipose depots and therefore adipose-secreted leptin, lipodystrophy mice with inducible pseudo-adipose depots as well as in vivo and ex vivo models of leptin supplementation. The use of several models to test the effect of adipose-secreted leptin on skeletal muscle yielded important data that suggest leptin is a regulator of muscle hypertrophy. Future work should aim to elucidate a mechanism that underlies these effects as well as testing the reproducibility of these findings in a non-lipodystrophy model. Collins et al. (2022) is an important paper for the understanding of the regulation of muscle mass and strength, and for the identification of adipose-produced leptin as a critical regulatory factor in proper muscle function. The researchers began by characterizing the difference in muscle mass and contractility in lipodystrophy/fat-free (FF) and wild-type (WT) mice. The researchers found that FF mice had a lower muscle mass and contractile performance than WT that was specific to the predominantly fast-twitch gastrocnemius and plantaris muscles, with no difference between groups in the mostly slow-twitch soleus. The differences in muscle were observed despite similar body weight compared with WT at 6 and 16 weeks of age. Further, it was the type 2B fibres that were observed to have a lower cross-sectional area in FF mice compared with control, leading the researchers to conclude that the FF mice were losing muscle mass via fast-fibre atrophy. In order to determine whether the muscle-specific effects observed in the lipodystrophy model were solely due to the loss of adipose, the FF mice were injected with mouse embryonic fibroblasts (MEF) to produce a spontaneous fat pad approximately 1 g in weight. The MEF-injected mice saw the gastrocnemius, plantaris and extensor digitorum longus muscles recovered to wild-type conditions, showing the importance of adipose tissue for muscle health. In the conditioned media from MEF explants, it was found that adipose-secreted IL-6, MCP-1, TNF-α, IL-1β, adiponectin and leptin were present in quantities similar to a normal visceral adipose depot, highlighting that the MEF pseudo-adipose depot does resemble a typical adipose depot in major adipokine secretion. Previous research in mice with impaired leptin signalling (ob/ob) yield deficits in muscle mass and contractility, primarily of fast-twitch muscles (Bruton et al., 2002), similar to what was observed in the lipodystrophy model. To further examine the specific role of leptin, they utilized MEF from ob/ob mice which lack leptin production (MEF-OB). The MEF-OB mice were found to have undetectable circulating leptin without affecting other adipokine levels and were therefore a valid model to examine the effects of specifically adipose-secreted leptin on skeletal muscle. It was found in that the MEF-induced recovery of muscle mass and contractility were lost in the MEF-OB mice, returning to levels observed in the FF mice. These results provide strong evidence that adipose-secreted leptin is regulating the parameters of muscle function measured. The researchers then sought to investigate how leptin exerts its control over muscle. Insulin sensitivity, hyperlipidaemia and glucocorticoids were measured, and it was found that the improved muscle mass and contractile function in the MEF mice were not mediated by any of these systemic factors. The researchers then took a group of FF mice and administered leptin (1 mg kg−1 body weight) or saline i.p. injections daily for a week to elucidate whether exogenous leptin supplementation could recover the loss of adipose leptin production. FF mice treated with leptin saw a significant increase in extensor digitorum longus and gastrocnemius muscle mass, although still lower than wild-type, indicating that exogenous leptin could partly recover muscle deficits brought forth by the loss of adipose tissue. The leptin-injected FF mice were observed to have higher markers of hypertrophy in gastrocnemius muscles (pAkt, and trending towards significance for pmTOR, and pS6 ribosomal protein made relative to total protein content). However, the higher hypertrophy markers in leptin-treated muscle could not be replicated in an ex vivo model of leptin supplementation. These results may point towards a factor that is present in the in vivo experiment and absent from the ex vivo experiment that mediates the leptin effect on muscle. Collins et al. (2022) utilized a model that allowed for both the study of the loss of adipose tissue and the loss of specifically adipose-secreted leptin which has yielded important data for the understanding of adipose–muscle crosstalk. It is, however, unknown whether the observed results could be replicated in a non-lipodystrophy model. In order to further solidify the importance of adipose-secreted leptin in muscle homeostasis, an adipose-specific leptin knockout with controlled food intake might be utilized to ensure that the findings brought forth can translate to a less metabolically perturbed model. As highlighted by the authors, the FF, MEF and MEF-OB groups were found to have impaired insulin sensitivity which would suggest that leptin's actions are independent of metabolic dysregulation. However, whether the observed effects translate to a model with less metabolic dysregulation should still be tested. Further, it is unclear whether the MEF-induced spontaneous fat pad can be compared to a typical adipose fat depot, since adipose depots are heterogeneous in the cell types present (Duerre & Galmozzi, 2022) and it is unknown whether this is true of the MEF pseudo-adipose depot. Additionally, the finding of fast-fibre atrophy in mice that lack leptin (FF and MEF-OB groups) is a striking finding and is in line with what is observed in ob/ob mice as well as other models of metabolic impairment. This might suggest that leptin dysregulation is a driving factor in the muscle remodelling secondary to metabolic challenge. The recovery of a low-level of leptin provided in the MEF group was found to attenuate this effect and brings forth the utility of leptin supplementation for the regulation of muscle mass. Further work should be undertaken to examine why it is that the fast-twitch glycolytic muscles are differentially impacted by the loss of leptin. The inability for leptin treatment to improve markers of hypertrophy in the ex vivo experiment may point to the indirect action of leptin on the regulation of muscle mass and contraction as brought forth by the authors in the discussion section. The authors hypothesize an adipose–liver–muscle or adipose–bone–muscle axis for leptin action; however, one additional mechanism worth further examination is the effect of leptin on muscle innervation. It is known that fast-twitch fibres have more active neuronal firing than slow-twitch fibres and there is evidence that the neurons that govern muscle innervation possess leptin receptors (Babic et al. 2010). Further study of leptin action at the neurons that innervate skeletal muscle warrants follow-up as this may explain the finding of beneficial effects of leptin supplementation in the in vivo but not the ex vivo experiments. Additionally, the known positive correlation between muscle innervation and hypertrophy would support further investigation into this hypothesis. In summary, Collins and colleagues have provided ample evidence in support of the importance of adipose tissue for skeletal muscle homeostasis, and adipose-derived leptin as a key regulator of muscle mass, hypertrophy and contractility. The work can be expanded upon to confirm that the observed effects translate to a potentially less metabolically perturbed adipose-specific leptin knockout model. The paper further uncovered a clue as to the function of leptin in muscle that should be studied in greater depth. Fast-fibre atrophy was observed in models with the lowest leptin levels (FF and MEF-OB) but is restored when leptin is present. Therefore, what was once thought to be a by-product of systemic dysregulation, fast-fibre atrophy, is directly dependent on leptin action. Future work should expand on the findings of this study to understand fully the mechanism and the scope of the governance of muscle form and function by leptin. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. A.R.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work M.F.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work None.

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