Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood.

One of cannabis' most iconic effects is the stimulation of hedonic high-calorie eating-the "munchies"-yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis' intoxicating constituent, Δ9-tetrahydrocannabinol (THC), to adolescent male mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and impaired cold- and ß-adrenergic receptor-stimulated lipolysis. Further analyses revealed that this phenotype is associated with molecular anomalies in the adipose organ, including ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring "pseudo-lean" state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.

Weight strategy in older adults with obesity: calorie restriction or not?

PURPOSE OF REVIEW: Along with the marked increase in the population of older adults with obesity is the need for effective strategies to treat aging- and obesity-related complications. This review highlights recent progress in obesity management in older adults. RECENT FINDINGS: Although calorie restriction is needed to significantly reduce fat mass, an exercise protocol is crucial to ameliorate functional outcomes. The addition of a resistance exercise protocol improves the response of muscle protein synthesis to anabolic stimuli, preventing the calorie restriction-induced reduction in muscle and bone mass. The addition of an aerobic exercise protocol improves cardiorespiratory fitness and cognitive function. However, the addition of both aerobic and resistance exercise protocols to calorie restriction provides the greatest improvements in myocellular quality, frailty, and cardiometabolic and cognitive outcomes, translating into the greatest improvement in quality of life. Such comprehensive lifestyle intervention effectively improves glucometabolic control and age-relevant outcomes in older adults with diabetes. When combined with testosterone therapy, such lifestyle intervention also preserves muscle and bone mass in older, men with obesity and hypogonadism. SUMMARY: We conclude that calorie restriction among older adults with obesity should be prescribed in combination with both aerobic and resistance exercise to maximize benefits on overall health.

Role of gremlin-1 in the pathophysiology of the adipose tissues.

Gremlin-1 is a secreted bone morphogenetic protein (BMP) antagonist playing a pivotal role in the regulation of tissue formation and embryonic development. Since its first identification in 1997, gremlin-1 has been shown to be a multifunctional factor involved in wound healing, inflammation, cancer and tissue fibrosis. Among others, the activity of gremlin-1 is mediated by its interaction with BMPs or with membrane receptors such as the vascular endothelial growth factor receptor 2 (VEGFR2) or heparan sulfate proteoglycans (HSPGs). Growing evidence has highlighted a central role of gremlin-1 in the homeostasis of the adipose tissue (AT). Of note, gremlin-1 is involved in AT dysfunction during type 2 diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) metabolic disorders. In this review we discuss recent findings on gremlin-1 involvement in AT biology, with particular attention to its role in metabolic diseases, to highlight its potential as a prognostic marker and therapeutic target.

Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy.

Context: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy. Objective: The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl. Methods: This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA). Results: Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed. Conclusion: T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

Lifestyle Intervention Strategy to Treat Diabetes in Older Adults: A Randomized Controlled Trial.

OBJECTIVE: Lifestyle intervention is recommended as first-line treatment of diabetes at all ages; however, little is known about the efficacy of lifestyle intervention in older adults with diabetes. We aimed to determine whether lifestyle intervention would improve glycemic control and age-relevant outcomes in older adults with diabetes and comorbidities. RESEARCH DESIGN AND METHODS: A total of 100 older adults with diabetes were randomly assigned to 1-year intensive lifestyle intervention (ILI) (diet and exercise at a facility transitioned into community-fitness centers and homes) or healthy lifestyle (HL) group. The primary outcome was change in HbA1c. Secondary outcomes included glucoregulation, body composition, physical function, and quality of life. Changes between groups were analyzed with mixed-model repeated-measures ANCOVA following the intention-to-treat principle. RESULTS: HbA1c improved more in the ILI than the HL group (mean ± SE -0.8 ± 0.1 vs. 0.1 ± 0.1%), associated with improved insulin sensitivity (1.2 ± 0.2 vs. -0.4 ± 0.2) and disposition (26.0 ± 8.9 vs. -13.0 ± 8.4 109 min-1) indices (between-group P < 0.001 to 0.04). Body weight and visceral fat decreased more in the ILI than HL group (-8.4 ± 0.6 vs. -0.3 ± 0.6 kg, P < 0.001, and -261 ± 29 vs. -30 ± 27 cm3, P < 0.001, respectively). Physical Performance Test score increased more in the ILI than HL group (2.9 ± 0.6 vs. -0.1 ± 0.4, P < 0.001) as did VO2peak (2.2 ± 0.3 vs. -1.2 ± 0.2 mL/kg/min, P < 0.001). Strength, gait, and 36-Item Short Form Survey (SF-36) Physical Component Summary score also improved more in the ILI group (all P < 0.001). Total insulin dose decreased in the ILI group by 19.8 ± 4.4 units/day. Adverse events included increased episodes of mild hypoglycemia in the ILI group. CONCLUSIONS: A lifestyle intervention strategy is highly successful in improving metabolic and functional health of older adults with diabetes.

Efficacy of the holistic, psychonutritional approach of Centro DAI e Obesità di Città della Pieve in the management of type 2 diabetes among patients with obesity and dysfunctional eating.

Purpose: Dysfunctional eating is strongly associated with obesity and worsens type 2 diabetes (T2DM) outcomes. The aim of this study was to investigate the effectiveness of the psycho-nutritional treatment (PNT) of "Centro DAI e Obesità" of Città della Pieve on weight loss and glucose management in dysfunctional eaters with obesity and T2DM. Methods: PNT includes psychotherapeutical, nutritional, physical and social activities. Subjects with obesity, T2DM and dysfunctional eating habits who completed the 8 weeks residential program between 2010 and 2019 were compared with obese, T2DM, dysfunctional eaters who underwent to a conventional, hospital-based, nutritional treatment (CT). Anthropometric variables, glucolipid panel, and body composition were assessed at baseline and at the end of the program. Weight and HbA1c were also measured after one year from the completion. Results: Sixty-nine patients completed the PNT and reduced weight (-7 ± 3.2%; p < 0.001), BMI (-7 ± 3.1%; p < 0.001), and triglycerides, AST, GGT and ALT (p ≤ 0.008); glycemic control improved (HbA1c: -1.1 ± 1.5%, mean fasting glucose: -41 ± 46 mg/dl, p < 0.001). Eleven% of subjects requiring diabetes medications at baseline discontinued the therapy. In the insulin treated group (49%), mean daily units were halved (-32.6 ± 26.0, p < 0.001). At one year, weight loss (-6 ± 7.4%, p < 0.001) and HbA1c reduction (-0.52 ± 1.4%, p = 0.029) persisted. Fifty-five patients completed the CT: HbA1c reduced (p = 0.02), but weight (-0.6 ± 3.7%), BMI (-0.7 ± 3.8%), and insulin units' reduction (-2.5 ± 11.7, p = 0.20) were lower compared to the PNT. Conclusion: PNT is effective in improving T2DM management in patients with obesity and dysfunctional eating.

One-Year Mean A1c of > 7% is Associated with Poor Bone Microarchitecture and Strength in Men with Type 2 Diabetes Mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM. METHODS: This was a secondary analysis of baseline data from 169 male participants, aged 35-65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography. RESULTS: At the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively). CONCLUSION: Poor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality.

A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

Brown Fat Anatomy in Humans and Rodents.

The Brown Adipose Tissue (BAT) is composed by mitochondrial rich, multilocular adipocytes, in strict topographical and functional relation with vasculature and noradrenergic nerves. Brown adipocytes are able to dissipate energy to produce heat, in a process known as non-shivering thermogenesis. Due to its contribution to energy expenditure, BAT is intensely studied for its potential to counteract metabolic diseases such as obesity, type 2 diabetes, dyslipidemia and cardiovascular diseases. BAT displays specific morphological characteristics that allow to assess its functional state. In this chapter we describe methodologies to properly dissect BAT depots, evaluate their gross anatomy, and assess its activation by light microscopy using peroxidase immunostaining and by laser scanning confocal microscopy using immunofluorescence. We also describe methodologies to study BAT ultrastructure by transmission and scanning electron microscopy, to visualize peroxidase immunostaining reactions at an ultrastructural level and to perform immunofluorescence reactions on paraffin-embedded samples, more often available in the clinical setting (due to the possibility to store them long-term) as opposed to fresh samples. The described techniques can be employed to study BAT morphology and activation in response to various stimuli (e.g., cold exposure; specific dietary composition) and in different pathological conditions (e.g., obesity; type 2 diabetes).

Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?

Obesity disease results from a dysfunctional modulation of the energy balance whose master regulator is the central nervous system. The neural circuitries involved in such function complete their maturation during early postnatal periods, when the brain is highly plastic and profoundly influenced by the environment. This phenomenon is considered as an evolutionary strategy, whereby metabolic functions are adjusted to environmental cues, such as food availability and maternal care. In this timeframe, adverse stimuli may program the body metabolism to maximize energy storage abilities to cope with hostile conditions. Consistently, the prevalence of obesity is higher among individuals who experienced early life stress (ELS). Oxytocin, a hypothalamic neurohormone, regulates the energy balance and modulates social, emotional, and eating behaviors, exerting both central and peripheral actions. Oxytocin closely cooperates with leptin in regulating energy homeostasis. Both oxytocin and leptin impact the neurodevelopment during critical periods and are affected by ELS and obesity. In this review article, we report evidence from the literature describing the effect of postnatal ELS (specifically, disorganized/inconstant maternal care) on the vulnerability to obesity with a focus on the role of oxytocin. We emphasize the existing research gaps and highlight promising directions worthy of exploration. Based on the available data, alterations in the oxytocin system may in part mediate the ELS-induced susceptibility to obesity.

Visceral fat inflammation and fat embolism are associated with lung's lipidic hyaline membranes in subjects with COVID-19.

BACKGROUND: Preliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19). METHODS: We performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied. RESULTS: Although there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects' lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed. CONCLUSIONS: This study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.

From Obesity to Diabetes: The Role of the Adipose Organ.

Obesity is a complex, multifactorial, and relapsing disease whose prevalence has tripled during the last decades and whose incidence is expected to further increase. For these reasons, obesity is considered as a real pandemic, deeply burdening the global health-care systems. From a pathophysiological standpoint obesity is the result of a chronic-positive energy balance which in turn leads to an excessive accumulation of lipids, not only within the adipose organ, but also in different cytotypes, a phenomenon leading to lipotoxicity that deeply compromises several cellular and organs functions. Obesity is therefore associated with over 200 medical complications, including insulin resistance and type 2 diabetes mellitus (T2DM) and represents the fifth leading cause of death worldwide. In this review, we describe the main pathophysiological mechanisms linking obesity-induced adipose organ dysfunction to insulin resistance and T2DM.

Aging, obesity, sarcopenia and the effect of diet and exercise intervention.

The number of adults 65 years and older is increasing worldwide and will represent the 20% of the population by 2030. Half of them will suffer from obesity. The decline in muscle mass and strength, known as sarcopenia, is very common among older adults with obesity (sarcopenic obesity). Sarcopenic obesity is strongly associated with frailty, cardiometabolic dysfunction, physical disability, and mortality. Increasing efforts have been hence made to identify effective strategies able to promote healthy aging and curb the obesity pandemic. Among these, lifestyle interventions consisting of diet and exercise protocols have been extensively explored. Importantly, diet-induced weight loss is associated with fat, muscle, and bone mass losses, and may further exacerbate age-related sarcopenia and frailty outcomes in older adults. Successful approaches to induce fat mass loss while preserving lean and bone mass are critical to reduce the aging- and obesity-related physical and metabolic complications and at the same time ameliorate frailty. In this review article, we discuss the most recent evidence on the age-related alterations in adipose tissue and muscle health and on the effect of calorie restriction and exercise approaches for older adults with obesity and sarcopenia, emphasizing the existing gaps in the literature that need further investigation.

High-Fat Diet Impairs Mouse Median Eminence: A Study by Transmission and Scanning Electron Microscopy Coupled with Raman Spectroscopy.

Hypothalamic dysfunction is an initial event following diet-induced obesity, primarily involving areas regulating energy balance such as arcuate nucleus (Arc) and median eminence (ME). To gain insights into the early hypothalamic diet-induced alterations, adult CD1 mice fed a high-fat diet (HFD) for 6 weeks were studied and compared with normo-fed controls. Transmission and scanning electron microscopy and histological staining were employed for morphological studies of the ME, while Raman spectroscopy was applied for the biochemical analysis of the Arc-ME complex. In HFD mice, ME ß2-tanycytes, glial cells dedicated to blood-liquor crosstalk, exhibited remarkable ultrastructural anomalies, including altered alignment, reduced junctions, degenerating organelles, and higher content of lipid droplets, lysosomes, and autophagosomes. Degenerating tanycytes also displayed an electron transparent cytoplasm filled with numerous vesicles, and they were surrounded by dilated extracellular spaces extending up to the subependymal layer. Consistently, Raman spectroscopy analysis of the Arc-ME complex revealed higher glycogen, collagen, and lipid bands in HFD mice compared with controls, and there was also a higher band corresponding to the cyanide group in the former compared to the last. Collectively, these data show that ME ß2-tanycytes exhibit early structural and chemical alterations due to HFD and reveal for the first-time hypothalamic cyanide presence following high dietary lipids consumption, which is a novel aspect with potential implications in the field of obesity.

Recruitment and remodeling of peridroplet mitochondria in human adipose tissue.

Beige adipocyte mitochondria contribute to thermogenesis by uncoupling and by ATP-consuming futile cycles. Since uncoupling may inhibit ATP synthesis, it is expected that expenditure through ATP synthesis is segregated to a disparate population of mitochondria. Recent studies in mouse brown adipocytes identified peridroplet mitochondria (PDM) as having greater ATP synthesis and pyruvate oxidation capacities, while cytoplasmic mitochondria have increased fatty acid oxidation and uncoupling capacities. However, the occurrence of PDM in humans and the processes that result in their expansion have not been elucidated. Here, we describe a novel high-throughput assay to quantify PDM that is successfully applied to white adipose tissue from mice and humans. Using this approach, we found that PDM content varies between white and brown fat in both species. We used adipose tissue from pheochromocytoma (Pheo) patients as a model of white adipose tissue browning, which is characterized by an increase in the capacity for energy expenditure. In contrast with control subjects, PDM content was robustly increased in the periadrenal fat of Pheo patients. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM compared to cytoplasmic mitochondria (CM). PDM isolated from periadrenal fat of Pheo patients had increased ATP-linked respiration, Complex IV content and activity, and maximal respiratory capacity. We found similar changes in a mouse model of re-browning where PDM content in whitened brown adipose tissue was increased upon re-browning induced by decreased housing temperature. Taken together, this study demonstrates the existence of PDM as a separate functional entity in humans and that browning in both mice and humans is associated with a robust expansion of peri-droplet mitochondria characterized by increased ATP synthesis linked respiration.

Testosterone therapy and bone quality in men with diabetes and hypogonadism: Study design and protocol.

CONTEXT: Type 2 diabetes mellitus (T2D) is often accompanied by male hypogonadism and both conditions are associated with increased risk for fractures. Testosterone (T) has been shown to improve the bone health of hypogonadal men but has not been tested in patients who also have T2D in addition to low T. To date, there is no treatment that is specifically recommended for bone disease among patients with T2D. This study will evaluate the effect of T therapy on the bone health of male veterans with low T who also have T2D. METHODS: This is a randomized double-blind placebo-controlled trial of 166 male veterans 35-65 years old, with T2D and hypogonadism, randomized to either T gel 1.62% or placebo for 12 months. We will evaluate the effect of T therapy on the following primary outcomes:1) changes in bone strength as measured by microfinite elements analysis (µFEA) using high-resolution peripheral quantitative computer tomography, 2) changes in bone turnover markers, and 3) changes in circulating osteoblast progenitors (COP) and osteoclast precursors cells. DISCUSSION: We anticipate that T therapy will result in improvement in bone strength owing to improvement in bone remodeling through an increase in osteoblastic differentiation and proliferation in patients with hypogonadism and T2D.

Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes.

CONTEXT: Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk. OBJECTIVE: Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared with hypogonadal men without T2D. METHODS: Single arm, open-label clinical trial (NCT01378299) involving 105 men (40-74 years old), with average morning testosterone <300 ng/dL. Subjects were injected intramuscularly with testosterone cypionate (200 mg) every 2 weeks for 18 months. Testosterone and estradiol were assessed by liquid chromatography/mass spectrometry; serum C-terminal telopeptide of type I collagen (CTX), osteocalcin and sclerostin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography. RESULTS: Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups. Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared with non-T2D men (P < .01). T2D men increased lumbar spine aBMD (P < .05), total area at 38% tibia (P < .01) and periosteal and endosteal circumferences at the same site (P < .01 for both). T2D men had reduced tibial vBMD (P < .01), but preserved bone mineral content (P = .01). Changes in HbA1c or body composition were similar between the 2 groups. CONCLUSION: Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their nondiabetic counterparts.

Mammary gland adipocytes in lactation cycle, obesity and breast cancer.

The mammary gland (MG) is an exocrine gland present in female mammals responsible for the production and secretion of milk during the process of lactation. It is mainly composed by epithelial cells and adipocytes. Among the features that make the MG unique there are 1) its highly plastic properties displayed during pregnancy, lactation and involution (all steps belonging to the lactation cycle) and 2) its requirement to grow in close association with adipocytes which are absolutely necessary to ensure MG's proper development at puberty and remodeling during the lactation cycle. Although MG adipocytes play such a critical role for the gland development, most of the studies have focused on its epithelial component only, leaving the role of the neighboring adipocytes largely unexplored. In this review we aim to describe evidences regarding MG's adipocytes role and properties in physiologic conditions (gland development and lactation cycle), obesity and breast cancer, emphasizing the existing gaps in the literature which deserve further investigation.

In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength and Low Bone Turnover.

INTRODUCTION: Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture, and strength in the obese population remains unknown. METHODS: Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay, body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry, whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography. Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D. RESULTS: Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49 ±â€…3.0 and 6.03 ±â€…2.47 vs 4.24 ±â€…2.72 ng/mL, respectively, P = 0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28 ±â€…0.10 and 0.29 ±â€…0.13 vs 0.21 ±â€…0.15 ng/mL, respectively, P = 0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (P = 0.003) and CTx (P = 0.005), greater trabecular separation at the tibia and radius (P = 0.03 and P = 0.04, respectively), and lower tibial failure load and stiffness (both P = 0.04), relative to obese men without T2D. CONCLUSION: In men, the combination of obesity and T2D is associated with reduced bone turnover and poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D, suggesting worse bone disease.