**1. Introduction**

Cachexia in chronic kidney disease (CKD) results in profound loss of adipose tissue and muscle mass [1,2]. Although poor protein-calorie intake is a major factor, growth hormone (GH) resistance has been linked to CKD-associated cachexia [1–4]. GH increases muscle strength in healthy men [5]. Short-term administration of recombinant GH increases muscle protein synthesis and muscle mass as well as improves quality of life in hemodialysis patients [6–10]. However, most studies have used dual energy X-ray absorptiometry (DXA) to measure muscle mass as a surrogate marker for the effect of GH treatment in hemodialysis patients, but the validity of this extrapolation in CKD is questionable since DXA cannot differentiate between a true increase in muscle mass versus fluid overload [11]. Moreover, the effect of GH on muscle function in CKD has not been adequately studied [12]. We have previously described the pathways involved in muscle wasting in a mouse model of CKD [13]. IGF-I and myostatin represent yin-and-yang signaling pathways in the

**Citation:** Mak, R.H.; Gunta, S.; Oliveira, E.A.; Cheung, W.W. Growth Hormone Improves Adipose Tissue Browning and Muscle Wasting in Mice with Chronic Kidney Disease-Associated Cachexia. *Int. J. Mol. Sci.* **2022**, *23*, 15310. https:// doi.org/10.3390/ijms232315310

Academic Editors: Márcia Carvalho and Luís Belo

Received: 3 October 2022 Accepted: 1 December 2022 Published: 4 December 2022

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pathogenesis of CKD-associated cachexia muscle wasting [14]. GH resistance in CKD, due to signal transduction defects in JAK-STAT pathways, is associated with upregulated SOCS-2 and downregulated IGF-I in skeletal muscle [15]. Myostatin is overexpressed in CKD-associated wasting and is accompanied by increased protein degradation via FoxOs, Atrogin-1, and MuRF-1, and decreased myogenesis via Pax3 and MyoD [13].

Adipose tissue regulates whole-body energy metabolism. White adipose tissue (WAT) is a key energy reservoir, while brown adipose tissue (BAT) is involved in the regulation of thermogenesis [16]. Recent studies have demonstrated that WAT browning, a process characterized by a phenotypic transition from WAT to thermogenic BAT, is implicated in the pathogenesis of cachexia. Indeed, browning of WAT preceded skeletal muscle atrophy in mouse models of CKD and cancer [17,18]. GH regulates adipose tissue metabolism [19,20]. In this study, we investigate the effects and mechanisms of GH in a mouse model of CKD, with emphasis on adipose tissue browning and muscle wasting.
