Two different types of adipose depots can be observed in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). The primary role of WAT is to deposit surplus energy in the form of triglycerides, along with many metabolic and hormonal activities; as thermogenic tissue, BAT has the distinct characteristic of using energy and glucose consumption as a strategy to maintain the core body temperature. Under specific stimuli—such as exercise, cold exposure, and drug treatment—white adipocytes can utilize their extraordinary flexibility to transdifferentiate into brown-like cells, called beige adipocytes, thereby acquiring new morphological and physiological characteristics. For this reason, the process is identified as the ‘browning of WAT’. We evaluated the ability of some drugs, including GW501516, sildenafil, and rosiglitazone, to induce the browning process of adult white adipocytes obtained from differentiated mesenchymal stromal cells (MSCs). In addition, we broadened our investigation by evaluating the potential browning capacity of IRISIN, a myokine that is stimulated by muscular exercises. Our data indicate that IRISIN was effective in promoting the browning of white adipocytes, which acquire increased expression of UCP1, increased mitochondrial mass, and modification in metabolism, as suggested by an increase of mitochondrial oxygen consumption, primarily in presence of glucose as a nutrient. These promising browning agents represent an appealing focus in the therapeutic approaches to counteracting metabolic diseases and their associated obesity.

• mesenchymal stem cells
• polyphenols
• senescence
• senolytics

• Aging/drug effects
• Cell Proliferation/drug effects
• Cellular Senescence/drug effects
• DNA Damage/drug effects
• Humans
• Mesenchymal Stem Cells/drug effects
• Senotherapeutics/pharmacology
• Stilbenes/pharmacology

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs’ intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS.

• aging
• mesenchymal stem cells
• senescence
• senolytics
• senomorphics

Mesenchymal stromal cells (MSCs), present in the stromal component of several tissues, include multipotent stem cells, progenitors, and differentiated cells. MSCs have quickly attracted considerable attention in the clinical field for their regenerative properties and their ability to promote tissue homeostasis following injury. In recent years, MSCs mainly isolated from bone marrow, adipose tissue, and umbilical cord—have been utilized in hundreds of clinical trials for the treatment of various diseases. However, in addition to some successes, MSC-based therapies have experienced several failures. The number of new trials with MSCs is exponentially growing; still, complete results are only available for a limited number of trials. This dearth does not help prevent potentially inefficacious and unnecessary clinical trials. Results from unsuccessful studies may be useful in planning new therapeutic approaches to improve clinical outcomes. In order to bolster critical analysis of trial results, we reviewed the state of art of MSC clinical trials that have been published in the last six years. Most of the 416 published trials evaluated MSCs’ effectiveness in treating cardiovascular diseases, GvHD, and brain and neurological disorders, although some trials sought to treat immune system diseases and wounds and to restore tissue. We also report some unorthodox clinical trials that include unusual studies.

• Clinical trials
• Mesenchymal stem cells
• Stem cells
• Stromal cells

• BAT
• WAT
• adipogenesis
• browning
• mesenchymal stromal cells

• ATP levels
• DNA repair
• Rett syndrome
• autophagy
• mesenchymal stromal cells
• metabolism
• mitochondrial ATP
• proteasome
• senescence

• Animals
• Cellular Senescence
• DNA Repair
• Disease Models, Animal
• Female
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/physiology
• Methyl-CpG-Binding Protein 2/genetics
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria/metabolism
• Mutation
• Rett Syndrome/metabolism
• Rett Syndrome/physiopathology

Research on physiopathology of obesity may receive new hints from studies on skinny people (SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.

To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells (MSCs).

We isolated MSCs from bone marrow of healthy donors with both normal body mass index (BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people (NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.

SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.

Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.

• Mesenchymal stromal cells
• Senescence
• Cytokines
• Adipogenesis
• Brown fat