Chewing the Fat: A Metabolic Role for Ldb1 Beyond the Pancreas?

The prevalence of obesity worldwide has reached epidemic proportions, with huge implications for health care costs and health outcomes related to comorbidities, such as dyslipidemia and diabetes, and subsequent complications (1–5). Challenges and limitations associated with traditional lifestyle changes, as well as more aggressive therapies, such as medications or bariatric surgery, have led researchers to search for alternative approaches to improve metabolic health (6–8).

Because of its roles in energy storage, insulin resistance, and inflammation, adipose tissue has emerged as a player in the physiologic response to energy excess (9). Over the past decade, the development of modern functional imaging techniques has allowed researchers to identify the presence of metabolically active brown adipose tissue (BAT) in adult humans (10–13). This discovery has led to a pronounced interest in the study of BAT, which regulates baseline and adaptive thermogenesis through the uncoupling of mitochondrial oxidative phyosphorylation to adenosine triphosphate synthesis (9). Specifically, through increased expression of uncoupling protein 1 and generation of heat, BAT is capable of dissipating excess energy accumulated through overconsumption (9, 14, 15). Furthermore, BAT is reduced in obese humans, suggesting that activation of BAT thermogenesis could potentially be harnessed to therapeutically increase energy expenditure (11). Additionally, rodent studies have suggested that activation of BAT could lead to other metabolic benefits, such as improved lipid profiles (16).

In their article published in this issue of Endocrinology, Loyd and colleagues (17) identify an exciting role played by the transcriptional coregulator LIM (Lin11-Isl1-Mec3) domain-binding protein 1 (Ldb1) in BAT biology. Ldb1 has previously been demonstrated to be important in determination of pancreatic endocrine precursor fate as well as maintenance of β-cell differentiation (18–20). However, other metabolic effects of Ldb1 have not previously been explored. On the basis of the observation that Ldb1 haploinsufficiency led to high-fat diet (HFD)–induced weight gain despite reductions in HFD intake, the authors measured energy expenditure (EE) in wild-type mice compared with global Ldb1 heterozygotes. Consistent with the observed HFD phenotype, Ldb1 heterozygotes displayed reduced EE and impaired BAT thermogenesis gene expression compared with controls. To ensure that observed differences were not related to reductions in circulating insulin (due to effects of reduced β-cell Ldb1 on β-cell identity and function), the authors used β cell–specific Ldb1 knockout mice, which exhibit hypoinsulinemia, as an alternative control, and were not able to measure any differences in EE or BAT gene expression.

Chromatin immunoprecipitation analysis identified a previously unrecognized interaction between Ldb1 and the promoter domain for the Elovl3 (elongation of very long chain fatty acid 3) gene. Because Elovl3 encodes a fatty acyl chain elongase that is important for formation of BAT very-long-chain fatty acids and triglycerides, regulation of Elovl3 expression could have major impacts on BAT recruitment and activity (21, 22). On the basis of the reduced expression observed in other key BAT genes among Ldb1 heterozygotes and the known importance of Ldb1 as a major coregulator in other organ systems, it is tempting to speculate that Ldb1 could also function as a critical regulator of BAT gene expression in general.

Because Ldb1 itself lacks nucleic acid–binding capacity or enzymatic activity, it typically exerts its influence through associations with other transcriptional regulators, such as proteins in the LIM-domain protein family, forming functional complexes that are subsequently able to affect transcriptional machinery (20, 23–27). Although chromatin immunoprecipitation identified Ldb1 enrichment of the Elovl3 promoter, at this point, it is unclear which additional proteins are necessary to enact Ldb1-mediated effects on BAT gene expression. Specifically, the authors were unable to detect BAT expression of Islet-1, a LIM-only transcription factor important for many Ldb1-mediated effects in the islet (18, 19). Further elucidation of the components of the Ldb1 complexes in BAT will be important next steps to understanding their contributions to BAT physiology.

Interestingly, although the authors were able to link reductions in EE and adaptive thermogenesis to increases in HFD-associated weight gain, haplo-insufficient mice on a normal diet were smaller than their counterparts, despite similar reductions in EE as mice on an HFD. Similar to the distinct roles of Ldb1 in β-cell development and maintenance of β differentiation, differences in baseline metabolic phenotype versus responses to challenges of HFD or cold stress could be related to differences in effects of reduced Ldb1 expression on BAT development versus maintenance of differentiation and function (18, 19). Alternatively, discrepancies in baseline and HFD phenotypes could be due to effects in other metabolic tissues beyond the pancreas and BAT. Certainly, Ldb1 complexes have been demonstrated to play important roles in regulation of transcription in numerous other systems (24, 28–31). The authors’ observations of high Ldb1 expression levels in other metabolic tissues, such as the brain, white adipose tissue, liver, and skeletal muscle, would suggest that the metabolic influence of Ldb1 reaches beyond the pancreas and BAT. Effects in these tissues seem especially likely to be contributing to the phenotype of global Ldb1 heterozygosity, given the observed improvements in insulin sensitivity, which seem at odds with observations of reduced BAT activity. Further studies are indicated to more fully explore the specific contributions of BAT as well as other tissues on Ldb1-related regulation of EE.

One clear aim of research involving BAT has been development of therapeutic agents that enhance BAT thermogenesis to increase EE (16). Along these lines, one could envision treatments that modulate Ldb1’s prothermogenic effects. However, because of the overarching roles of this transcriptional coregulator in multiple organ systems, a clearer understanding of Ldb1’s BAT targets and coeffectors will be crucial to identify BAT-specific drugs and avoid off-target effects. Nonetheless, this important contribution substantially advances our knowledge of the role of Ldb1 and its potential relevance to human energy homeostasis.