Leptin is a circulating hormone secreted by adipose tissue which acts as a signal to the central nervous system where it regulates energy homeostasis and neuroendocrine processes. Although leptin modulates the secretion of several pituitary hormones, no information is available regarding a direct action of pituitary products on leptin release. However, it has been pointed out that leptin and TSH have a coordinated pulsatility in plasma. In order to test a direct action of TSH on in vitro leptin secretion, a systematic study of organ cultures of human omental adipose tissue was performed in samples obtained at surgery from 34 patients of both sexes during elective abdominal surgery. TSH powerfully stimulated leptin secretion by human adipose tissue in vitro. In contrast, prolactin, ACTH, FSH and LH were devoid of action. These results suggest that leptin and the thyroid axis maintain a complex and dual relationship and open the possibility that plasmatic changes in TSH may contribute to the regulation of leptin pulses.
Polymerase mu (Polμ) is an error-prone, DNA-directed DNA polymerase that participates in non-homologous end-joining (NHEJ) repair. In vivo, Polμ deficiency results in impaired Vκ-Jκ recombination and altered somatic hypermutation and centroblast development. In Polμ−/− mice, hematopoietic development was defective in several peripheral and bone marrow (BM) cell populations, with about a 40% decrease in BM cell number that affected several hematopoietic lineages. Hematopoietic progenitors were reduced both in number and in expansion potential. The observed phenotype correlates with a reduced efficiency in DNA double-strand break (DSB) repair in hematopoietic tissue. Whole-body γ-irradiation revealed that Polμ also plays a role in DSB repair in non-hematopoietic tissues. Our results show that Polμ function is required for physiological hematopoietic development with an important role in maintaining early progenitor cell homeostasis and genetic stability in hematopoietic and non-hematopoietic tissues.
Combined deficiencies of poly(ADP)ribosyl polymerase 1 (PARP1) and ataxia telangiectasia mutated (ATM) result in synthetic lethality and, in the mouse, early embryonic death. Here, we investigated the genetic requirements for this lethality via analysis of mice deficient for PARP1 and either of two ATM-regulated DNA damage response (DDR) factors: histone H2AX and 53BP1. We found that, like ATM, H2AX is essential for viability in a PARP1-deficient background. In contrast, deficiency for 53BP1 modestly exacerbates phenotypes of growth retardation, genomic instability, and organismal radiosensitivity observed in PARP1-deficient mice. To gain mechanistic insights into these different phenotypes, we examined roles for 53BP1 in the repair of replication-associated double-strand breaks (DSBs) in several cellular contexts. We show that 53BP1 is required for DNA-PKcs-dependent repair of hydroxyurea (HU)-induced DSBs but dispensable for RPA/ RAD51-dependent DSB repair in the same setting. Moreover, repair of mitomycin C (MMC)-induced DSBs and sister chromatid exchanges (SCEs), two RAD51-dependent processes, are 53BP1 independent. Overall, our findings define 53BP1 as a main facilitator of nonhomologous end joining (NHEJ) during the S phase of the cell cycle, beyond highly specialized lymphocyte rearrangements. These findings have important implications for our understanding of the mechanisms whereby ATM-regulated DDR prevents human aging and cancer.DNA double-strand breaks (DSBs) arise constantly in mammalian cells from endogenous and exogenous sources (35). Defective DSB repair leading to cellular senescence or apoptosis, or aberrant repair to form chromosomal rearrangements, has been linked to aging and cancer in humans (22, 31). To prevent these deleterious outcomes, mammalian cells have evolved the DNA damage response (DDR), a network of factors that sense and signal DSBs to promote their repair (29). ataxia telangiectasia mutated (ATM) is a phophoinositide 3-kinase (PI3K)-like kinase that regulates the functions of hundreds of substrates during DDR, including histone H2AX and 53BP1 (41). Ultimately, the DDR restores DNA strand continuity via either of two main DSB repair pathways: homologous recombination (HR), an error-free pathway that operates only during the S/G 2 phases (70), or nonhomologous end joining (NHEJ), a versatile but error-prone pathway that operates throughout the cell cycle (37, 44).Poly(ADP)ribosyl polymerase 1 (PARP1) regulates, among other processes, transcription, cell death, and DNA repair (57). In the last context, PARP1 senses single-strand breaks (SSBs) and promotes their repair via base excision repair (BER) (15). Although PARP1 is not a component of the BER pathway per se, PARP1-deficient cells accumulate SSBs, which become substrates for HR-mediated repair upon replication (10, 21). ATM and other DDR factors may play important roles in DSB recognition and recruitment of the HR machinery in this setting (42). In addition, PARP1 also catalyzes PAR formation at de novo-generated DNA DSBs (28...
A definitive consequence of the aging process is the progressive deterioration of higher cognitive functions. Defects in DNA repair mechanisms mostly result in accelerated aging and reduced brain function. DNA polymerase µ is a novel accessory partner for the non-homologous end-joining DNA repair pathway for double-strand breaks, and its deficiency causes reduced DNA repair. Using associative learning and long-term potentiation experiments, we demonstrate that Polµ−/− mice, however, maintain the ability to learn at ages when wild-type mice do not. Expression and biochemical analyses suggest that brain aging is delayed in Polµ−/− mice, being associated with a reduced error-prone DNA oxidative repair activity and a more efficient mitochondrial function. This is the first example in which the genetic ablation of a DNA-repair function results in a substantially better maintenance of learning abilities, together with fewer signs of brain aging, in old mice.
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