Carlos Escande

The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200–800 mg) in healthy lean volunteers; (B) multiple ascending doses (200–400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment. Overall, SANA appears to be a first-in-class activator of creatine-dependent energy expenditure and thermogenesis, highlighting its potential as a therapeutic candidate for ‘diabesity’. Australian New Zealand Clinical Trials Registry registration: ACTRN12622001519741.

The protein Deleted in Breast Cancer 1 (Dbc1) is an important regulator of various transcription factors and epigenetic modulators, significantly influencing metabolism, obesity, and aging-related processes. Knockout mice lacking Dbc1 exhibit severe obesity but remain protected from liver steatosis, insulin resistance, and atherosclerosis. We hypothesized that this phenotype of “healthy obesity” results from adipose tissue expansion, which prevents free fatty acid spillover and subsequent metabolic damage to peripheral tissues. To further investigate the putative role of Dbc1 in adipose cells during obesity and its effects on metabolic dysregulation, we generated conditional Dbc1 knockout (KO) mice by backcrossing with AdipoQ-CRE transgenic mice to selectively abrogate Dbc1 expression in all mature adipocytes (Dbc1^LoxP/LoxP;CRE). These mice demonstrated effective deletion of Dbc1 in mature adipocytes across various fat depots. We assessed the impact of Dbc1 deletion on metabolic regulation in male and female mice fed standard chow and high-fat diets. Our findings revealed that Dbc1 knockout in mature adipocytes did not influence weight gain, glucose tolerance, or other metabolic dysregulation markers, irrespective of sex. However, Dbc1 KO adipocytes exhibited an mRNA expression profile indicative of heightened inflammation during obesity. These results suggest that the protective phenotype observed in whole-body Dbc1 KO obese mice is not attributable to Dbc1’s function within mature adipocytes but likely involves other cell types in adipose tissue. Moreover, the specific deletion of Dbc1 in mature adipocytes unveils a novel role of Dbc1 in inflammation signaling during obesity.

The protein Deleted in Breast Cancer 1 (DBC1), a regulator of several transcription factors and epigenetic modulators, plays determinant roles in metabolism regulation, obesity and aging-related processes. Knockout mice for Dbc1, develop morbid obesity but are protected against liver steatosis, insulin resistance and atherosclerosis. We have proposed that this healthy obesity phenotype was mainly due to the expansion of adipose tissue, avoiding free-fatty acid spillover and metabolic damage in peripheral tissues. To gain more insight about the role of Dbc1 in adipose cells during obesity and its impact on metabolic dysregulation, we generated a conditional Dbc1 KO mouse and backcrossed it with CRE-AdipoQ transgenic mice, aiming to abrogate Dbc1 expression in all mature adipocytes (cAT-Dbc1). cAT-Dbc1 mice showed deletion of Dbc1 specifically in mature adipocytes in different fat depots. We tested the effect of Dbc1 deletion in adipocytes on different aspects of metabolic regulation in male and female mice fed in normal chow and high-fat diets. We found that deletion of Dbc1 in mature adipocytes had no effect on weight gain, glucose tolerance and other markers of metabolic dysregulation, regardless sex. However, Dbc1 KO adipocytes displayed an mRNA expression profile consistent with increased inflammation during obesity. Our results suggest that the healthy phenotype displayed in the whole body Dbc1 KO obese mice is not due to the protein function in mature adipocytes and might involve other cell types present in adipose tissue. Instead, the specific deletion of Dbc1 in mature adipocytes highlights a novel role of Dbc1 in inflammation signaling during obesity.

FSTL1 is a secreted glycoprotein that is involved in several processes in health and disease, including development, cardiovascular disease, cancer, inflammation, and obesity. The signaling pathways used by FSTL1 to act on target tissues seem to activate different intracellular mediators specific to each tissue and several of the mechanisms of action remain to be determined at the molecular level, including intracellular mediators and receptors. We have previously unveiled a novel role for FSTL1 in ciliogenesis and provided evidence for an Fstl1/cilia axis in preadipocyte differentiation. This pathway is relevant to the pathogenesis of obesity and of a group of conditions called ciliopathies since they are caused by the dysfunction of the primary cilia. This work aimed to identify intracellular mediators of FSTL1 action on ciliogenesis and adipogenesis. We analyzed ERK phosphorylation levels as well as cilia length in the absence of FSTL1 and in the presence of the pERK inhibitor U0126. We also analyzed the differentiation and cilia dynamics of U0126-treated preadipocytes and tested the ERK-mediated signaling by BMP4 in the presence of added extracellular Fstl1. Here, we propose that MAP kinase ERK is a mediator of ciliogenesis downstream of FSTL1 and provide additional data that suggest that FSTL1 antagonizes BMP non-canonical signaling to modulate ciliogenesis and adipogenesis. In sum, our data reinforce the interest on the axis FSTL1/cilia in the modulation of adipogenesis and provide evidence to add ERK to this working model.

Significance: Sirtuins are NAD ⁺ -dependent histone deacetylases regulating important processes in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis. Recent Advances: Despite initially being discovered to regulate transcription and life span via histone deacetylase activities, emerging data continually uncover new targets and propose additional roles. Due to the outstanding importance of the sirtuins in the control of the inflammatory response, their roles in the pathogenesis of several inflammatory-based diseases have become an area of intense research. Although sirtuins have been traditionally regarded as anti-inflammatory players, several recent findings suggest that their role in inflammation is complex and that in some cases sirtuins can indeed promote inflammation. Critical Issues: In this article, we provide an update on the latest findings concerning the new mechanisms of action and concepts about the role of sirtuins during inflammation. We focus on the impact that inflammatory-based processes exert on the liver, adipose tissue, and nervous system as well as on macrophage function and activation. Also, we discuss available data pointing to the dual role that, in particular contexts, sirtuins may have on inflammation control. Future Directions: Since the knowledge of sirtuin impact on metabolism is continually expanding, new venues of research arise. Besides become being regarded as candidates of therapeutic targets, posttranscriptional control of sirtuin expression by means of microRNAs challenges our traditional concepts of sirtuin regulation; importantly, the emerging role of NAD ⁺ metabolism in aging and longevity has added a new dimension to the interest in sirtuin function. Antioxid. Redox Signal. 39, 1185–1208.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

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CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of aCcdc28bmutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype.Ccdc28b mutanimalsi)do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues,ii)reproduce normally, andiii)do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast,Ccdc28b mutmice did show clear social interaction defects as well as stereotypical behaviors. This finding is indeed relevant regardingCCDC28Bas a modifier of BBS since behavioral phenotypes have been documented in BBS. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution ofCCDC28Bto modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link betweenCCDC28Band behavioral defects, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of these complex phenotypes.