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Uncoupling proteins (UCPs) are transmembrane proteins members of the mitochondrial anion transporter family present in the mitochondrial inner membrane. Currently, six homologs have been identified (UCP1-6) in mammals, with ubiquitous tissue distribution and multiple physiological functions. UCPs are regulators of key events for cellular bioenergetic metabolism, such as membrane potential, metabolic efficiency, and energy dissipation also functioning as pivotal modulators of ROS production and general cellular redox state. UCPs can act as proton channels, leading to proton re-entry the mitochondrial matrix from the intermembrane space and thus collapsing the proton gradient and decreasing the membrane potential. Each homolog exhibits its specific functions, from thermogenesis to regulation of ROS production. The expression and function of UCPs are intimately linked to diabesity, with their dysregulation/dysfunction not only associated to diabesity onset, but also by exacerbating oxidative stress-related damage. Male infertility is one of the most overlooked diabesity-related comorbidities, where high oxidative stress takes a major role. In this review, we discuss in detail the expression and function of the different UCP homologs. In addition, the role of UCPs as key regulators of ROS production and redox homeostasis, as well as their influence on the pathophysiology of diabesity and potential role on diabesity-induced male infertility is debated.

Obesity is one of the most challenging health issue worldwide that has been steadily increasing in the last decades. Obesity arises from a positive energy balance in result of increased intake and decreased energy expenditure, usually due to inadequate dietary habits and a sedentary lifestyle, which results in the accumulation of excess body fat. There are few pharmacological tools to address obesity, thus calorie restriction and increased physical activity are still the cornerstone of obesity treatment. In recent years, natural products obtained from plants have been thoroughly studied to infer whether these have any potential to target obesity. Methylxanthines comprise one of those classes of compounds that are abundant in common food products consumed on a daily basis worldwide, such as coffee, chocolate, or tea. Despite caffeine is the most popular and well-studied methylxanthine, theobromine and theophylline are also abundant in humans’ diet. Notably, methylxanthines proved to stimulate lipolysis and inhibit adipogenesis, which are interesting properties that could contribute for obesity management. This review aims to discuss the most recent information concerning the promising role of methylxanthines in the modulation of adipose tissue functions, highlighting the potential of these molecules in the development of novel therapeutic approaches for obesity treatment.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel responsible for the direct transport of bicarbonate and chloride. CFTR-dependent ionic transport is crucial for pH regulation and fluid homeodynamics among epithelial surfaces. Particularly, CFTR performs an essential role in the male reproductive tract, which requires a tight regulation of water and electrolytes in order to produce healthy spermatozoa. The absence or malfunction of CFTR results in cystic fibrosis, the most common lethal disease among Caucasians, that is characterized by an impaired fluid and ionic homeostasis in the whole organism. Due to the wide expression and importance of CFTR, the male reproductive tract is highly affected by cystic fibrosis, resulting in male infertility. Although CFTR is not permeable to water, this protein acts as a regulator of other protein channels, such as aquaporins. In fact, CFTR acts as a molecular partner of aquaporins in epithelial cells, regulating fluid homeodynamics. Herein, up-to-date data concerning the regulation of aquaporin-mediated water transport by CFTR will be discussed, highlighting the role of both channels in the male reproductive tract.

Adipocytes are the most abundant cells within the adipose tissue and are the cell type responsible for the tissue dynamic metabolic and endocrine activity. Under energy surplus conditions, the adipocyte is able to suffer hypertrophy in order to accommodate energy in form of lipids. Simultaneously, new adipocytes are differentiated through a complex and specific process, known as adipogenesis. While this process seems clear for white adipocytes in white adipose tissue, brown adipocytes and brown adipose tissue have distinct characteristics and function. Brown adipocytes are not related with fat accumulation but rather with thermogenesis, a process defined by a rapidly oxidization of lipids in order to produce heat. Additionally, a class of beige adipocytes, which are inducible thermogenic adipocytes originating from white adipose tissue and phenotypically distinct from both, have been described though how these are originated and which are the main functions are still matters of discussion. Interestingly, the induction of thermogenesis seems to improve insulin resistance, adiposity and hyperlipidemia. Thus, inducing the browning of white adipocytes to beige adipocytes is thought to be promising to improve the common metabolic disorders, such as obesity or metabolic syndrome. This chapter focuses on the specific signaling and regulatory control of adipocyte functions, particularly adipogenesis and adipocyte browning. Emerging insights of these processes are herein discussed, as promising therapeutic targets for obesity and other common metabolic disorders.

Spermatozoa capacitation is a complex process that requires specific ionic and energetic conditions to support biochemical alterations leading to motility hyperactivation. However, human sperm capacitation is still poorly understood. Herein, we studied the effects of glucose on human sperm capacitation. Healthy men seminal samples (n = 55) were submitted to a density gradient centrifugation and incubated in capacitating conditions in the absence or presence of increasing glucose concentrations (0, 5.5, 11, and 22 mM). Viability and total motility were accessed. Phosphotyrosine levels were measured. Mitochondrial activity and endogenous ROS production were evaluated. Oxidative stress-induced damage was analyzed. Culture media was collected and analyzed by1H-NMR. Our results show that glucose is essential for human sperm capacitation and motility. Notably, we observed that mitochondrial activity increased even in the absence of glucose. This increased mitochondrial activity was followed by a ROS overproduction, although no oxidative stress-induced damage was detected. Our results show that glucose is essential for capacitation but mitochondrial activation is independent from its stimuli. ROS overproduction may take part on a finely regulated signaling pathway that modulates or even activates capacitation. Taken together, our results constitute a paradigm shift on human sperm capacitation physiology. The work was co-funded by FEDER through the COMPETE/QREN, FSE/POPH to Marco G. Alves (IFCT2015, PTDC/MEC-AND/28691/2017), UMIB (PEst-OE/SAU/UI0215/2019) and QOPNA (UID/QUI/00062/2019); co-funded by the EU Framework Programme for Research and Innovation H2020 (POCI/COMPETE2020). This work was supported by “Fundação para a Ciência e a Tecnologia”—FCT to David F. Carrageta (SFRH/BD/136779/2018) and Bárbara Guerra-Carvalho (PTDC/MEC-AND/28691/2017).

In the male reproductive tract, ionic equilibrium is essential to maintain normal spermatozoa production and, hence, the reproductive potential. Among the several ions, HCO3- and H+ have a central role, mainly due to their role on pH homeostasis. In the male reproductive tract, the major players in pH regulation and homeodynamics are carbonic anhydrases (CAs), HCO3- membrane transporters (solute carrier 4-SLC4 and solute carrier 26-SLC26 family transporters), Na+-H+ exchangers (NHEs), monocarboxylate transporters (MCTs) and voltage-gated proton channels (Hv1). CAs and these membrane transporters are widely distributed throughout the male reproductive tract, where they play essential roles in the ionic balance of tubular fluids. CAs are the enzymes responsible for the production of HCO3- which is then transported by membrane transporters to ensure the maturation, storage, and capacitation of the spermatozoa. The transport of H+ is carried out by NHEs, Hv1, and MCTs and is essential for the electrochemical balance and for the maintenance of the pH within the physiological limits along the male reproductive tract. Alterations in HCO3- production and transport of ions have been associated with some male reproductive dysfunctions. Herein, we present an up-to-date review on the distribution and role of the main intervenient on pH homeodynamics in the fluids throughout the male reproductive tract. In addition, we discuss their relevance for the establishment of the male reproductive potential.

High 17&beta, Estradiol (E2) levels are known to cause alterations of spermatogenesis and environments throughout the male reproductive tract. Sertoli cells (SCs) ensure an adequate environment inside the seminiferous tubule. Glycerol stands as essential for the maintenance of blood&ndash, testis barrier created by SCs, however, the role of E2 in this process is not known. Herein, we hypothesized that the effect of E2 on glycerol permeability in mouse SCs (mSCs) could be mediated by aquaglyceroporins. The expression of aquaglyceroporins was assessed by RT-PCR and qRT-PCR. Glycerol permeability was evaluated by stopped-flow light scattering. We were able to identify the expression of AQP3 and AQP9 in mSCs where AQP9 is more abundant than AQP3. Our results show that high E2 levels decrease AQP9 mRNA abundance with no influence on AQP3 in mSCs. Interestingly, high E2 levels decreased mSCs&rsquo, permeability to glycerol, while downregulating AQP9 expression, thus suggesting a novel mechanism by which E2 modulates fluid secretion in the testis. In conclusion, E2 is an important regulator of mSCs physiology and secretion through changes in AQP9 expression and function. Thus, alterations in glycerol permeability induced by E2 may be the cause for male infertility in cases associated with the presence of high E2 levels.