IN OBESITY, INSULIN RESISTANCE AND ARTERIAL HYPERTENSION ARE ASSOCIATED WITH THE DEVELOPMENT OF CARDIOVASCULAR DISEASES AND INCREASED MORTALITY RISK. TIME RESTRICTED FEEDING (TRF) HAS EMERGED AS A DIETARY INTERVENTION THAT CAN HELP COUNTERACT THE CONSEQUENCES OF OBESITY. IN THE PRESENT REVIEW, WE ANALYZE TRF EFFECTS AND ITS APPLICATION ON INSULIN RESISTANCE AND HIGH BLOOD PRESSURE. FINALLY, WE DISCUSS OTHER FACTORS UNDERLYING CARDIOMETABOLIC EFFECTS AND PROVIDE PRACTICAL CONSIDERATIONS.

AUTOPHAGY IS UPREGULATED IN ADIPOSE TISSUE (AT) FROM PEOPLE WITH OBESITY. WE SHOWED THAT ACTIVATION OF THE CALCIUM-SENSING RECEPTOR (CASR) ELEVATES PROINFLAMMATORY CYTOKINES THROUGH AUTOPHAGY IN PREADIPOCYTES. OUR AIM IS TO UNDERSTAND THE ROLE OF CASR ON AUTOPHAGY IN AT FROM HUMANS WITH OBESITY. WE DETERMINED MRNA AND PROTEIN LEVELS OF CASR AND MARKERS OF AUTOPHAGY BY QPCR AND WESTERN BLOT IN HUMAN VISCERAL AT EXPLANTS OR ISOLATED PRIMARY PREADIPOCYTES (60 DONORS: 72% FEMALE, 23-56% BODY FAT). WE ALSO INVESTIGATED THEIR ASSOCIATION WITH DONORS ANTHROPOMETRIC VARIABLES. DONORS % BODY FAT AND CASR MRNA EXPRESSION IN AT WERE CORRELATED (R = 0.44, P < 0.01). CASR EXPRESSION WAS ASSOCIATED WITH MRNA LEVELS OF THE AUTOPHAGY MARKERS ATG5 (R = 0.37, P < 0.01), ATG7 (R = 0.29, P < 0.05) AND LC3B (R = 0.40, P < 0.01). CASR ACTIVATION INCREASED BECN AND ATG7 MRNA EXPRESSION IN AT. CASR ACTIVATION ALSO UPREGULATED LC3II BY ~50%, AN EFFECT ABOLISHED BY THE CASR INHIBITOR. SPERMINE (CASR AGONIST) REGULATES LC3II THROUGH THE ERK1/2 PATHWAY. STRUCTURAL EQUATION MODEL ANALYSIS SUGGESTS A LINK BETWEEN DONORS AT CASR EXPRESSION, AT AUTOPHAGY AND EXPRESSION OF TUMOR NECROSIS FACTOR ALPHA TNF-?. CASR EXPRESSION IN VISCERAL AT IS DIRECTLY ASSOCIATED WITH % BODY FAT, AND CASR ACTIVATION MAY CONTRIBUTE TO OBESITY-RELATED DISRUPTION IN AT AUTOPHAGY.

OBESITY IS CHARACTERIZED BY A CHRONIC INFLAMMATORY PROCESS, WITH AN INCREASED VOLUME OF TOTAL ADIPOSE TISSUE, ESPECIALLY VISCERAL, WHICH SECRETES PRO-INFLAMMATORY CYTOKINES SUCH AS TNF-? AND IL-6. HEPCIDIN (HPC), A MAIN IRON METABOLISM REGULATOR, IS SYNTHETIZED BY AN IL-6 STIMULI, AMONG OTHERS, IN LIVER AND ADIPOSE TISSUE, FAVORING AN ASSOCIATION BETWEEN THE INFLAMMATORY PROCESS AND IRON METABOLISM. STILL THERE ARE QUESTIONS REMAIN REGARDING THE INTERACTION OF THESE FACTORS. OUR AIM WAS TO STUDY THE EFFECT OF A MACROPHAGE-CONDITIONED MEDIUM (MCM) ON ADIPOCYTE CELLS CHALLENGED WITH GLUCOSE AND/OR IRON. WE STUDIED THE MRNA RELATIVE ABUNDANCE OF GENES RELATED TO INFLAMMATION IN DIFFERENTIATED 3T3-L1 CELLS CHALLENGED WITH FE (40 ?M), GLUCOSE (20 MM) OR FE/GLUCOSE (40 ?M/20 MM) WITH OR WITHOUT MCM FOR 24 H. WE ALSO MEASURED THE INTRACELLULAR IRON LEVELS UNDER THESE CONDITIONS. OUR RESULTS SHOWED THAT WHEN ADIPOCYTES WERE CHALLENGED WITH MCM, GLUCOSE AND/OR FE, THE INTRACELLULAR IRON AND MRNA LEVELS OF PRO-INFLAMMATORY CYTOKINES INCREASED. THESE RESPONSES WERE HIGHER WHEN ALL THE STIMULI WERE COMBINED WITH MCM FROM MACROPHAGES. THUS, WE SHOWED THAT COMBINED HIGH GLUCOSE/HIGH FE ALONE OR WITH MCM MAY CONTRIBUTE TO AN INCREASE ON INTRACELLULAR IRON AND INFLAMMATORY RESPONSE IN 3T3-L1 DIFFERENTIATED CELLS, BY INCREASED MRNA LEVELS OF IL-6, TNF-?, MCP-1, HPC AND REDUCING ADIPONECTIN LEVELS, ENHANCING THE INFLAMMATORY PROCESSES.

HYPOTHYROIDISM IS A COMMON ENDOCRINE DISORDER IN THE POPULATION, RESULTING FROM A DECREASE IN THE FUNCTION OF THE THYROID GLAND AND AFFECTING THE THYROID HORMONE PRODUCTION. THIS PATHOLOGY HAS SEVERAL HEALTH IMPLICATIONS, AND ITS CLINICAL MANAGEMENT EXTENDS BEYOND CONVENTIONAL PHARMACOLOGICAL TREATMENT. NUTRITION IS RELATED TO THE THYROID GLAND FUNCTION, HOWEVER, NUTRITIONAL RECOMMENDATIONS BASED ON RECENT SCIENTIFIC EVIDENCE HAVE NOT BEEN DETERMINED. THE PRESENT REVIEW ADDRESSES THE PATHOGENESIS OF HYPOTHYROIDISM, FOLLOWED BY AN UPDATED APPROACH TO NUTRIENTS AND FOODS ASSOCIATED WITH THYROID FUNCTION.

PECTINS ARE A TYPE OF SOLUBLE FIBER PRESENT IN NATURAL AND PROCESSED FOODS. EVIDENCE REGARDING THE EFFECT OF ESTERIFICATION DEGREE OF PECTINS ON IRON ABSORPTION IN HUMANS IS SCARCE. IN THE PRESENT STUDY, THE EFFECT OF PECTINS WITH DIFFERENT DEGREES OF ESTERIFICATION ON NON-HEME IRON ABSORPTION IN WOMEN WAS EVALUATED. A CONTROLLED EXPERIMENTAL STUDY WAS CONDUCTED WITH BLOCK DESIGN, INVOLVING 13 APPARENTLY HEALTHY, ADULT WOMEN. EACH SUBJECT RECEIVED 5 MG FE (FESO4) WITHOUT PECTIN (CONTROL) OR ACCOMPANIED BY 5 G CITRUS PECTIN, TWO WITH A LOW DEGREE OF ESTERIFICATION (27 AND 36%), AND ONE WITH A HIGH DEGREE OF ESTERIFICATION (67 TO 73%), EACH ON DIFFERENT DAYS. EACH DAY, THE 5 MG FE DOSES WERE MARKED WITH RADIOACTIVE FE-59 OR FE-55. RADIOACTIVITY INCORPORATED INTO ERYTHROCYTES WAS DETERMINED IN BLOOD SAMPLES 14 DAYS AFTER THE MARKED FE DOSES WERE CONSUMED. ON DAYS 18 AND 36 OF STUDY, 30 AND 20 ML BLOOD SAMPLES WERE OBTAINED, RESPECTIVELY, AND BLOOD SAMPLE RADIOACTIVITY INCORPORATED INTO ERYTHROCYTES WAS DETERMINED. BODY IRON STATUS WAS DETERMINED FROM BLOOD TAKEN ON DAY 18. WHOLE BODY BLOOD VOLUME WAS ESTIMATED FOR CALCULATE IRON BIOAVAILABILITY; IT WAS ASSUMED THAT 80% OF ABSORBED RADIOACTIVITY WAS INCORPORATED INTO THE HB. ALL WOMEN PARTICIPANTS SIGNED AN INFORMED CONSENT OF PARTICIPATION AT BASELINE. IRON BIOAVAILABILITY (MEAN GEOMETRIC +/- 1 SD) ALONE (CONTROL) WAS 18.2% (12.3-27.1%), IRON + PECTIN27 WAS 17.2% (10.2-29.2%), IRON + PECTIN36 WAS 15.3% (9.5-24.6%), AND IRON + PECTIN67 WAS 19.5% (10.0-38.0%). NO STATISTICALLY SIGNIFICANT DIFFERENCES BETWEEN IRON BIOAVAILABILITY (REPEATED MEASURES ANOVA, P = 0.22) WERE OBSERVED. PECTIN ESTERIFICATION DEGREE DOES NOT INFLUENCE THE BIOAVAILABILITY OF NON-HEME IRON IN WOMEN.

LIPOINFLAMATION IS THE INFLAMMATION GENERATED IN THE ADIPOSE TISSUE. IT CAN CONTRIBUTE TO THE DEVELOPMENT OF INSULIN RESISTANCE. THE LIPOINFLAMMATION-ASSOCIATED MECHANISMS ARE RELATED TO THE FUNCTION OF ADIPOCYTES AND MACROPHAGES PRESENT IN THE ADIPOSE TISSUE. IN THIS REGARD, THE LEVEL OF NUCLEOSIDE ADENOSINE IS INCREASED IN INDIVIDUALS WITH OBESITY. CAUSES OR CONSEQUENCES OF THIS INCREASE ARE UNKNOWN. ALTHOUGH, ADENOSINE ACTIVATING ITS RECEPTORS (A1, A2A, A2B AND A3) IS ABLE TO DIFFERENTIALLY MODULATE THE FUNCTION OF ADIPOCYTES AND MACROPHAGES, IN ORDER TO AVOID THE REDUCTION OF INSULIN SENSITIVITY AND GENERATE AN ANTI-INFLAMMATORY STATE IN SUBJECT WITH OBESITY. IN THIS REVIEW WE PROPOSE THAT ADENOSINE COULD BE A KEY ELEMENT IN THE DEVELOPMENT OF NEW STRATEGIES FOR LIMIT LIPOINFLAMMATION AND REGULATE METABOLIC HOMEOSTASIS THROUGH MODULATION OF ADIPOCYTE-MACROPHAGE DIALOGUE.

ADIPOSE TISSUE INFLAMMATION IN OBESITY HAS A DELETERIOUS IMPACT ON ORGANS SUCH AS THE LIVER, ULTIMATELY LEADING TO THEIR DYSFUNCTION. WE HAVE PREVIOUSLY SHOWN THAT ACTIVATION OF THECALCIUM-SENSING RECEPTOR (CASR) IN PRE-ADIPOCYTES INDUCES TNF-? AND IL-1? EXPRESSION AND SECRETION; HOWEVER, IT IS UNKNOWN WHETHER THESE FACTORS PROMOTE HEPATOCYTE ALTERATIONS, PARTICULARLY PROMOTING CELL SENESCENCE AND/OR MITOCHONDRIAL DYSFUNCTION. WE GENERATED CONDITIONED MEDIUM (CM) FROM THE PRE-ADIPOCYTE CELL LINE SW872 TREATED WITH EITHER VEHICLE (CMVEH) OR THE CASR ACTIVATOR CINACALCET 2 ?M (CMCIN), IN THE ABSENCE OR PRESENCE OF THE CASR INHIBITOR CALHEX 231 10 ?M (CMCIN+CAL). HEPG2 CELLS WERE CULTURED WITH THESE CM FOR 120 H AND THEN ASSESSED FOR CELL SENESCENCE AND MITOCHONDRIAL DYSFUNCTION. CMCIN-TREATED CELLS SHOWED INCREASED SA-?-GAL STAINING, WHICH WAS ABSENT IN TNF-?- AND IL-1?-DEPLETED CM. COMPARED TO CMVEH, CMCIN ARRESTED CELL CYCLE, INCREASED IL-1? AND CCL2 MRNA, AND INDUCED P16 AND P53 SENESCENCE MARKERS, WHICH WAS PREVENTED BY CMCIN+CAL. CRUCIAL PROTEINS FOR MITOCHONDRIAL FUNCTION, PGC-1? AND OPA1, WERE DECREASED WITH CMCIN TREATMENT, CONCOMITANT WITH FRAGMENTATION OF THE MITOCHONDRIAL NETWORK AND DECREASED MITOCHONDRIAL TRANSMEMBRANE POTENTIAL. WE CONCLUDE THAT PRO-INFLAMMATORY CYTOKINES TNF-? AND IL-1? SECRETED BY SW872 CELLS AFTER CASR ACTIVATION PROMOTE CELL SENESCENCE AND MITOCHONDRIAL DYSFUNCTION, WHICH IS MEDIATED BY MITOCHONDRIAL FRAGMENTATION IN HEPG2 CELLS AND WHOSE EFFECTS WERE REVERSED WITH MDIVI-1. THIS INVESTIGATION PROVIDES NEW EVIDENCE ABOUT THE DELETERIOUS CASR-INDUCED COMMUNICATION BETWEEN PRE-ADIPOCYTES AND LIVER CELLS, INCORPORATING THE MECHANISMS INVOLVED IN CELLULAR SENESCENCE.

THE COMPLEX PHYSIOLOGY OF EUKARYOTIC CELLS REQUIRES THAT A VARIETY OF SUBCELLULAR ORGANELLES PERFORM UNIQUE TASKS, EVEN THOUGH THEY FORM HIGHLY DYNAMIC COMMUNICATION NETWORKS. IN THE CASE OF THE ENDOPLASMIC RETICULUM (ER) AND MITOCHONDRIA, THEIR FUNCTIONAL COUPLING RELIES ON THE PHYSICAL INTERACTION BETWEEN THEIR MEMBRANES, MEDIATED BY DOMAINS KNOWN AS MITOCHONDRIA-ER CONTACTS (MERCS). MERCS ACT AS SHUTTLES FOR CALCIUM AND LIPID TRANSFER BETWEEN ORGANELLES, AND FOR THE NUCLEATION OF OTHER SUBCELLULAR PROCESSES. OF NOTE, MOUNTING EVIDENCE SHOWS THAT THEY ARE HETEROGENEOUS STRUCTURES, WHICH DISPLAY DIVERGENT BEHAVIORS DEPENDING ON THE CELL TYPE. FURTHERMORE, MERCS ARE PLASTIC STRUCTURES THAT REMODEL ACCORDING TO INTRA- AND EXTRACELLULAR CUES, THEREBY ADJUSTING THE FUNCTION OF BOTH ORGANELLES TO THE CELLULAR NEEDS. IN CONSONANCE WITH THIS NOTION, THE MALFUNCTION OF MERCS REPORTEDLY CONTRIBUTES TO THE DEVELOPMENT OF SEVERAL AGE-RELATED DISORDERS. HERE, WE INTEGRATE CURRENT LITERATURE TO DESCRIBE HOW MERCS CHANGE, STARTING FROM UNDIFFERENTIATED CELLS, AND THEIR TRANSIT THROUGH SPECIALIZATION, MALIGNANT TRANSFORMATION (I.E., DEDIFFERENTIATION), AND AGING/SENESCENCE. ALONG THIS JOURNEY, WE WILL REVIEW THE FUNCTION OF MERCS AND THEIR RELEVANCE FOR PIVOTAL CELL TYPES, SUCH AS STEM AND CANCER CELLS, CARDIAC, SKELETAL, AND SMOOTH MYOCYTES, NEURONS, LEUKOCYTES, AND HEPATOCYTES, WHICH INTERVENE IN THE PROGRESSION OF CHRONIC DISEASES RELATED TO AGE.