Michael D. Jensen

Prospective evaluation of Roux-en-Y gastric bypass as primary operation for medically complicated obesity

OBJECTIVEnTo determine prospectively the results of Roux-en-Y gastric bypass (RYGB) used as the primary weight-reducing operation in patients with medically complicated (morbid) obesity. The RYGB procedure combines the advantages of a restrictive physiology (pouch of 10 mL) and a dumping physiology for high-energy liquids without requiring an externally reinforced (banded) stoma.nnnPATIENTS AND METHODSnBetween April 1987 and December 1998, a total of 191 consecutive patients with morbid obesity (median weight, 138 kg [range, 91-240 kg]; median body mass index, 49 kg/m2 [range, 36-74 kg/m2]), all of whom had directly weight-related morbidity, underwent RYGB and prospective follow-up.nnnRESULTSnHospital mortality was 0.5% (1/191), and hospital morbidity occurred in 10.5% (20/191). Good long-term weight loss was achieved, and patients adapted well to the required new eating habits. The mean +/- SD weight loss at 1 year after operation (113 patients) was 52 +/- 1 kg or 68% +/- 2% of initial excess body weight. By 3 years postoperatively (74 patients), weight loss was still 66% +/- 2% of excess body weight. Overall, 53 (72%) of 74 patients had achieved and maintained a weight loss of 50% or more of their preoperative excess body weight 3 years after the operation. In addition, only 1 (1%) of 98 patients had persistent postoperative vomiting 1 or more times per week.nnnCONCLUSIONnWe believe that RYGB is a safe, effective procedure for most patients with morbid obesity and thus may be the current procedure of choice in patients requiring bariatrics++ surgery for morbid obesity.

The Long Form of the Leptin Receptor (OB-Rb) Is Widely Expressed in the Human Brain

Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin action is mediated by the interaction with a receptor that is alternatively spliced, resulting in at least five different isoforms. The long form (OB-Rb) has a long intracellular domain that is essential for intracellular signal transduction. The specific aim of this study was to further investigate the role that the brain may play in the pathogenesis of obesity in humans. We studied the expression of OB-R mRNA (both short or common and long isoforms) in the brains of obese, lean and diabetic subjects, by in situ hybridization, semiquantitative RT-PCR and Northern blots analysis. We used two alternative probes: one that recognizes all known splice variants (OB-Ra) and a second that recognizes only the long form, OB-Rb. Several brain regions, including hypothalamus, cerebellum, neocortex, entorrhinal cortex, amygdala, and rostral medulla, were evaluated. In situ hybridization studies revealed that both OB-Ra and OB-Rb mRNAs are widely distributed in the human brain. The specific hybridization signal with both probes was detected exclusively in the cytoplasm of the cell body, dendrites and proximal axons of neurons. Hypothalamic nuclei, Purkinje cells and dentate nuclei of the cerebellum, inferior olivary and cranial nerves nuclei in the medulla, amygdala and neurons from both neocortex and entorrhinal cortex demonstrated positive signals. The hybridization signal obtained in ependyma was lower than that in neurons and no specific hybridization was detected in glial cells. No significant differences were identified among the regions or among the three groups studied. These results match those previously obtained by us [Couce et al.: Neuroendocrinology 1997;66:145] in which the distribution of the OB-R protein in the human brain was first described. RT-PCR indicated that the OB-Rb was highly expressed in the hypothalamus and cerebellum. No significant differences of OB-Ra or OB-Rb mRNA expression were identified in lean or obese individuals in these two cerebral regions. The levels of OB-Rb were significantly higher in cerebellum compared to hypothalamus in lean and obese individuals. The original hypothesis that OB-Rb is present only in the hypothalamus needs to be reconsidered. This OB-Rb isoform seems to be widely expressed in the human brain with highest levels in the cerebellum. Obesity and hyperleptinemia appears not to be associated with down-regulation of the OB-Rb in the human brain.

Prospective evaluation of vertical banded gastroplasty as the primary operation for morbid obesity

Our previous experience with vertical (nonbanded) gastroplasty proved disappointing because of unsatisfactory maintenance of weight loss. Vertical banded gastroplasty seemed to be an attractive alternative operation because it provided an externally reinforced (banded) stoma that would not enlarge over time. In this study, our aim was to determine prospectively the results of vertical banded gastroplasty used as a primary, weight-reducing procedure in patients with morbid obesity. Seventy consecutive patients with morbid obesity (mean weight, 139 kg), all of whom had obesity-related complications, underwent vertical banded gastroplasty and prospective follow-up. The hospital mortality was nil, and substantial morbidity occurred in 3% (two patients). Long-term achievement and maintenance of satisfactory weight loss, however, were variable. The median weight loss at 1 year after operation was 36.7 kg or 48% of excess body weight. At 3 years postoperatively, however, weight loss was only 32.4 kg or 40% of excess body weight, and only 38% of patients had achieved and maintained a weight loss of 50% or more of their preoperative excess body weight. Vertical banded gastroplasty caused major changes in eating habits, and many patients were unable to eat red meat or untoasted bread; moreover, approximately 30 to 50% of patients continued to vomit once or more per week. Despite theoretically attractive advantages as a weight-reduction operation, vertical banded gastroplasty does not seem to be the optimal procedure for most patients with morbid obesity.

Treatment of toxic multinodular goiter (hummer's disease): Surgery or radioiodine?

The records of patients treated at the Mayo Clinic for toxic multinodular goiter during 1950–1954, 1960–1964, and 1970–1974 were reviewed to compare results of surgical and131I therapy, to define trends in treatment policy and outcome, and to attempt to elucidate factors associated with posttreatment hypothyroidism. The series involved 446 patients who underwent thyroidectomy as initial treatment and 89 who initially received131I. The time to success was significantly shorter (p=0.001) in surgically treated patients than in patients initially receiving131I. Compared with patients treated medically, patients treated initially with surgery were much less likely to require a second treatment (0% versus 24%) during the first year after initial treatment. The probability of postthyroidectomy hypothyroidism increased from approximately 12% in the 1950s to more than 70% in the 1970s at 2 years after surgery. Neither more aggressive surgery nor use of more sensitive tests to diagnose hypothyroidism accounted for the increased probability in recent years.RésuméLes dossiers de malades traités par les auteurs pour goitre multinodulaire toxique de 1950 à 1954, de 1960 à 1964, et de 1970 à 1974 ont été revus pour comparer les résultats respectifs du traitement chirurgical et du traitement par lI131, pour définir les tendances de lattitude thérapeutique et de lévolution, pour tenter délucider les facteurs associés à lhypothyroïdisme secondaire au traitement. Les 3 séries concernent 446 malades qui ont été traités par lI131. La période de temps nécessaire pour obtenir un bon résultat fut plus courte (p=0.001) chez les sujets traités chirurgicalement que chez ceux traités médicalement. Par comparaison avec ces derniers les premiers furent moins nombreux à recevoir un traitement secondaire de nécessité (0% contre 24%) au cours de la première année qui suivit le traitement initial. Le risque dhypothyroïdie secondaire à la thyroïdectomie, 2 ans après lintervention, sest élevé de 12% dans la première série à 70% dans la troisième. Laugmentation du risque au cours des années les plus récentes dépend ni dune attitude chirurgicale plus agressive ni de lemploi de tests plus sensibles pour dépister lhypothyroïdie.ResumenSe revisaron las historias clínicas de los pacientes con bocio tóxico multinodular tratados en el Mayo Clinic en los períodos 1950–1954, 1960–1964 y 1970–1974 con el objeto de comparar los resultados de la cirugía y de la terapia con131I, de definir las tendencias en las políticas terapéuticas y sus resultados, y de tratar de identificar factores asociados con el desarrollo de hipotiroidismo post tratamiento. La serie incluye 446 pacientes que fueron sometidos a tiroidectomía como tratamiento inicial y 89 que inicialmente recibieron131I. El intervalo entre el tratamiento y el efecto deseado fue significativamente más corto (p=0.001) en los pacientes tratados quirúrgicamente que en los pacientes que recibieron131I. Al compararlos con los pacientes de tratamiento médico, los pacientes inicialmente tratados con cirugía demostraron considerable menor necesidad de un segundo tratamiento (0% versus 24%) en el curso del primer año después del tratamiento inicial. La probabilidad de hipotiroidismo postirodectomía a los 2 años después de la cirugía aumentó de aproximadamente 12% en los años 1950s a más de 70% en los años 1970s. Ni la cirugía más agresiva ni el uso de métodos de diagnóstico del hipotiroidismo de mayor sensibilidad aparecen como factores de esta incrementada probabilidad observada en los años más recientes.

Pre-transplant wasting (as measured by muscle index) is a novel prognostic indicator in lung transplantation

Frailty in non‐transplant populations increases morbidity and mortality. Muscle wasting is an important frailty characteristic. Low body mass index is used to measure wasting, but can over‐ or underestimate muscle mass. Computed tomography (CT) software can directly measure muscle mass. It is unknown if muscle wasting is important in lung transplantation.

Brown adipose tissue – not as hot as we thought

The article by Blondin et al. (2015) in the current issue of The Journal of Physiology brings together and expands upon three adipose/muscle-related concepts that emphasize the importance of understanding physiology before jumping to conclusions when new findings are reported. n nFirst, the excitement following the reports of brown adipose tissue (BAT) in 2009 (Cypess etxa0al. 2009; van Marken Lichtenbelt etxa0al. 2009; Virtanen etxa0al. 2009) has spawned a number of additional, enthusiastic reports of human BAT activity (Orava etxa0al. 2011). Some authors suggest that BAT accounts for up to 20% of the cold-stimulated increase in energy expenditure in humans (Cypess etxa0al. 2009). In the rush to characterize BAT as the next frontier in obesity treatment investigators have largely ignored the obligate relationship between energy expenditure and oxygen delivery, which in turn is dependent upon blood flow and tissue mass. Adipose tissue blood flow is notoriously low relative to metabolically active tissues (Summers etxa0al. 1996; Karpe etxa0al. 2002), and it turns out that BAT is not an exception. Even during cold exposure BAT blood flow averages only 13xa0mlxa0(100xa0g tissue)−1xa0min−1 (Muzik etxa0al. 2012, 2013). Under conditions of normal oxygen saturation and 16xa0gxa0dl−1 of haemoglobin, 100xa0ml of arterial blood contains only 21.3xa0ml of O2. With an average total body BAT volume of 57xa0ml, the amount of oxygen delivered to total body BAT would be only ∼1.6xa0mlxa0min−1. Furthermore, BAT oxygen extraction is reported to be ∼56% (Muzik etxa0al. 2012). Thus, under steady-state, cold-stimulated conditions, average whole-body BAT oxygen consumption should be ∼1xa0mlxa0min−1, very similar to that measured using oxygen isotopes and PET approaches (Muzik etxa0al. 2012). This is underwhelming considering the cold-induced increase in oxygen uptake of ∼270xa0mlxa0min−1 that was observed by Blondin etxa0al. (2015). The BAT oxygen uptake data (Muzik etxa0al. 2012, 2013) are consistent with the limited total body BAT glucose uptake relative to the increase in total glucose disposal in response to cold (Blondin etxa0al. 2015). Even individuals at the high end of BAT blood flow (25xa0mlxa0(100xa0g tissue)−1xa0min−1; Orava etxa0al. 2011) and with 100xa0g of total body BAT, actual BAT thermogenesis would account for only ∼1% of the increase in energy expenditure above basal induced by cold exposure. n nThe second important observation is the contribution of subclinical muscle shivering to cold-induced increases in muscle glucose uptake and presumably energy expenditure. Blondin etxa0al.’s careful and extensive use of surface electromyography showed that muscle contraction (shivering) is the major component of the increase in whole-body glucose uptake. This suggests that investigations directed at the role of muscle, rather than BAT, will be more promising. n nFinally, the observation by Blondin etxa0al. (2015) that the cold-induced increase in non-esterified fatty acid release from adipose tissue lipolysis relates to the activation of BAT is important. It is consistent with animal data indicating that the sympathetic innervation of BAT and white adipose tissue (WAT) is similar (reviewed in Vaughan etxa0al. 2014). This implies that variations in sympathetic activation or the sensitivity to such activation is similar in human BAT and WAT. If the former, then variations in observed BAT activation during cold exposure could reflect more of a central nervous system sympathetic response to cold rather than a peripheral, e.g. BAT, difference. n nIn summary, the findings of Musik (Muzik etxa0al. 2012, 2013) and Blondin etxa0al. (2015) suggest to me that BAT is most likely a vestigial and largely irrelevant tissue when it comes to adult human energy expenditure. They also provide some renewed excitement about the role of muscle in resting energy expenditure.

Direct free fatty acid storage in different sized adipocytes from the same depot.

Human adipocytes take up free fatty acids (FFA) directly from the circulation, even at times of high lipolytic activity. Whether these processes occurs simultaneously within the same cells or are partitioned between different cells, for example large and small cells, is unknown.

Acute Female Hypogonadism Alters Adipose Tissue Fatty Acid Storage Factors and Chylomicronemia

CONTEXTnChronic sex steroid deficiency has effects on adipose fatty acid (FA) storage mechanisms and fat oxidation, but the chronology of events are not well understood.nnnOBJECTIVEnThe objective of the study was to examine the acute effects of female sex steroid suppression on cellular mechanisms affecting abdominal and femoral subcutaneous adipose tissue FA storage.nnnDESIGNnThis study had a randomized, longitudinal, parallel study design.nnnSETTINGnThe study was conducted at the Mayo Clinic Clinical Research Unit.nnnPARTICIPANTSnThirty-eight nonsmoking premenopausal women aged 18-50 years participated in the study.nnnINTERVENTIONnThe intervention included randomization to receive one of the following: 1) no treatment (control), 2) 3.75 mg of Lupron, or 3) 3.75 mg of Lupron and estrogen, but not progesterone, replacement for 49 days, resulting in at least 4 weeks of sex steroid suppression.nnnMAIN OUTCOME MEASURESnBody composition, fat cell size, postprandial chylomicron and nonchylomicron triglyceride concentrations, adipose tissue meal FA storage, direct free fatty acid storage, lipoprotein lipase, acyl CoA synthetase, and diacylglycerol acyltransferase activities, and CD36 content were measured.nnnRESULTSnCompared with the control group, the fed state femoral lipoprotein lipase activity was reduced in women taking Lupron and those taking Lupron and estrogen replacement. In addition, we observed significantly greater postprandial chylomicronemia in the Lupron group than in the other two groups. There were no differences in overall fat storage and oxidation. Depending on the mode of data expression (per unit lipid vs per 1000 adipocytes), there were modest changes in acyl CoA synthetase, diacylglycerol acyltransferase, and CD36 in response to acute sex hormone suppression.nnnCONCLUSIONSnOur results suggest estrogen and progesterone may have different effects on the regulation of FA metabolism and that acute sex steroid deficiency in women does not alter fat storage and oxidation.

Arterio-venous balance studies of skeletal muscle fatty acid metabolism: what can we believe?

The arterio-venous balance (A-V balance/difference) technique has been used by a number of groups, including ours, to study skeletal muscle fatty acid metabolism. Several lines of evidence indicate that, like glycogen, intramyocellular triglycerides (imcTG) are an energy source for local use. As such, the report that increased release of free fatty acids (FFA) via lipolysis from skeletal muscle, but not from adipose tissue, is responsible for the increased systemic lipolysis during IL-6 infusion in healthy humans is somewhat unexpected (26). It appears that given the complex anatomy of human limbs, as to be discussed in this review, it is virtually impossible to determine whether any fatty acids being released into the venous circulation of an arm or leg derive from the lipolysis of intermuscular fat residing between muscle groups, intramuscular fat residing within muscle groups (between epimysium and perimysium, or bundles), or the intramyocellular triglyceride droplets (imcTG). In many cases, it may even be difficult to be confident that there is no contribution of FFA from subcutaneous adipose tissue. This question is fundamentally important as one attempts to interpret the results of skeletal muscle fatty acid metabolism studies using the A-V balance technique. In this Perspectives article, we examine the reported results of fatty acid kinetics obtained using the techniques to evaluate the degree of and how to minimize contamination when attempting to sample skeletal muscle-specific fatty acids.

Relationship between insulin sensitivity and long-term weight change in adults.

OBJECTIVEnTo determine whether insulin resistance is associated with reduced risk of weight gain.nnnMETHODSnIn this retrospective study, we reviewed medical records of volunteers who had undergone a euglycemic, hyperinsulinemic clamp in research studies at Mayo Clinic between October 20, 1986, and January 30, 2002. Data from volunteers who had at least 1 year of followup were analyzed, which included height, weight, date of birth, ethnicity, body composition (percentage body fat and kilograms of fat-free mass), waist-to-hip ratio, date of insulin clamp, fasting plasma glucose and insulin, average plasma glucose and insulin concentrations during the final 30 minutes of each insulin clamp step, and average glucose infusion rate (μmol·kg fat free mass⁻¹·min⁻¹) during the final 30 minutes of each insulin clamp step. We abstracted the following for each medical encounter: date of visit, height, weight, diagnoses, procedures, and medication use. For the purposes of statistical analysis, the diagnoses, procedures, and medications were then converted into Current Procedural Terminology codes and National Drug Codes.nnnRESULTSnOne hundred sixteen patients had at least 1 year of follow-up. The average baseline body mass index was 29.4 ± 5.3 kg/m², and the follow-up time averaged 8.1 ± 5.9 years. We found no significant correlation between baseline insulin action and annual weight change or overall weight change (P = .60 and P = .11, respectively) or between log-transformed insulin action and annual weight gain (P = .61).nnnCONCLUSIONnThese results suggest that in free-living, healthy, white adults, there is not a clinically meaningful relationship between insulin action and subsequent weight change.