Adipose FHL1 in energy homeostasis

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SUMMARY Tremendous advances have been made in the study of adipose biology but there are gaps in our understanding of adipose development and functions. The long-term goal of our research is to understand how adipose tissues regulate whole-body energy metabolism, insulin sensitivity and glucose homeostasis. To achieve these goals, we have developed cellular and animal models to study the effects of gene perturbations in relation to adipose tissues development. One such gene is Four-and-half-LIM domain 1 (FHL1), a protein highly expressed in skeletal and cardiac muscles, and has recently been implicated in human adipose tissue development. A case report on a 15-year old patient with a complete deletion of FHL1 with adjacent MAP7D3 gene exhibited a near total loss of adipose tissues accompanied by muscular hypertrophy, rigid spine and short stature. The specific role of FHL1 in adipose development and function is unknown. In preliminary experiments, we identified FHL1 as a major co-transcription factor of PPARg, suggesting a role in transcriptional regulation of adipose tissues. To mimic the loss of adipose tissues in the human patient, we created a mouse model where FHL1 is globally deficient. Whole body Fhl1 knockout mice were resistant to diet-induced obesity (DIO). Interestingly, a previous study has shown that mice lacking a related paralog, FHL2, are also resistant to DIO. We found that FHL1 deficiency in murine preadipocytes partially attenuated differentiation into adipocytes, and a single amino acid substitution from tryptophan to serine at position 122 within FHL1 specifically abrogated PPARg isoform 2 (PPARg2) expression, but not isoform 1 (PPARg1). In agreement, knockdown of FHL1 in human adipocytes preferentially reduced PPARg2 expression, but not PPARg1. It has been reported that PPARg2 is adipose- specific, necessary and sufficient in activation of adipogenesis in fibroblast. In addition to activation of PPARg, FHL1 cooperates with PPARg in activation of PPARg-dependent gene expression. Based on our preliminary data, we hypothesized that FHL1 regulates adipocyte differentiation, at least in part, through transcriptional regulation of PPARg. This proposal seeks to investigate the cellular, molecular and physiological mechanisms by which FHL1 regulates adipose tissue development and energy homeostasis. Specific Aim 1 will examine the roles of FHL1 and FHL2 in murine adipocyte differentiation. Specific Aim 2 will address the underlying molecular mechanisms linking FHL1 and transcriptional regulation of adipocyte differentiation. Specific Aim 3 will investigate the in vivo functions of FHL1 in adipose-specific knockout mice and in human transplant models. Together, the proposed experiments will provide mechanistic insights into adipose biology, pathophysiology of obesity, potentially lead to novel therapeutic strategies for obesity and related metabolic diseases.