Moderating "the great debate": The carbohydrate-insulin vs. the energy balance models of obesity.

The increased prevalence of obesity in recent decades is a topic of great scientific and medical interest, but despite many advances, the causes of this increase have not been adequately identified. In this context, two conflicting models for obesity-the carbohydrate-insulin model (CIM) and the energy balance model (EBM)-are being vigorously debated by distinct cohorts of experts in the field. The goal of this perspective is to assess this "conflict of models" from a neutral perspective. I conclude that although both models have produced useful insights, they differ fundamentally in what they seek to explain, and neither has yet provided a validated mechanistic account for the rising obesity prevalence in some but not all members of the population. Rather than engaging in such debates over competing models, the field should be more focused on establishing specific mechanistic insights in identified patient groups and, eventually, actionable interventions based on them.

The Diversity of Institutions Conducting Biomedical Research.

Biomedical research in the United States has contributed enormously to science and human health and is conducted in several thousand institutions that vary widely in their histories, missions, operations, size, and cultures. Though these institutional differences have important consequences for the research they conduct, the organizational taxonomy of US biomedical research has received scant systematic attention. Consequently, many observers and even participants are surprisingly unaware of important distinguishing attributes of these diverse institutions. This essay provides a high-level taxonomy of the institutional ecosystem of US biomedical research; illustrates key features of the ecosystem through portraits of eight institutions of varying age, size, culture, and missions, each representing a much larger class exhibiting additional diversity; and suggests topics for future research into the research output of institutional types that will be required to develop novel approaches to improving the function of the ecosystem.

Publishing Biomedical Research: a rapidly evolving ecosystem.

The advancement of science requires the publication of research results so other scientists may examine, confirm, and build upon them, and the publishing ecosystem that mediates this process has undergone dramatic change over recent decades. This article takes a broad view of the biomedical research publishing system from its origins in the 17th century to the present day. It begins with a story from the author's lab that illustrates a scientist's complex interactions with the publishing system and then reviews the history, growth, and evolution of scientific publishing, including several recent disruptive developments: the digital transformation, the open access (OA) movement, the creation of "predatory journals," and the emergence of preprint archives. Each has influenced scientific peer review and editorial decision-making, two processes critical to the conduct of medical and scientific research and culture. After briefly discussing concerns about the impact of politics on editorial decision-making, the article closes with thoughts on the future evolution of this publishing ecosystem, which will impact the biomedical research ecosystem that depends upon it. Beyond accelerated speed and improved access to publications, the community should prioritize research aimed at further enhancing the quality and impact of published research, the core goal of the scientific enterprise.

The Problem of Irreproducible Bioscience Research.

Over recent decades, progress in bioscience research has been remarkable, but alongside the many transformative advances is a growing concern that a surprisingly high fraction of published research cannot be reproduced by the scientific community. Though experimental and interpretive errors are unavoidable features of the scientific process, recent evidence suggests that irreproducibility is a serious issue requiring analysis, understanding, and remediation. This article reviews the meaning of research reproducibility, examines ongoing efforts to estimate its prevalence, and considers the factors that contribute to it. Two recent case studies illustrate the disparate responses that researchers may take when facing serious claims that a high-profile research finding is irreproducible and may be false. Finally, the article examines potential interventions to counter the current level of irreproducibility, aimed at increasing the efficiency and impact of society's substantial and critically important investment in bioscience research.

Misconduct in Bioscience Research: a 40-year perspective.

Fraud in biomedical research, though relatively uncommon, damages the scientific community by diminishing the integrity of the ecosystem and sending other scientists down fruitless paths. When exposed and publicized, fraud also reduces public respect for the research enterprise, which is required for its success. Although the human frailties that contribute to fraud are as old as our species, the response of the research community to allegations of fraud has dramatically changed. This is well illustrated by three prominent cases known to the author over 40 years. In the first, I participated as auditor in an ad hoc process that, lacking institutional definition and oversight, was open to abuse, though it eventually produced an appropriate result. In the second, I was a faculty colleague of a key participant whose case helped shape guidelines for management of future cases. The third transpired during my time overseeing the well-developed if sometimes overly bureaucratized investigatory process for research misconduct at Harvard Medical School, designed in accordance with prevailing regulations. These cases illustrate many of the factors contributing to fraudulent biomedical research in the modern era and the changing institutional responses to it, which should further evolve to be more efficient and transparent.

Insulin: A pacesetter for the shape of modern biomedical science and the Nobel Prize.

BACKGROUND: The 100th anniversary of the discovery of insulin in Toronto in 1921 is an important moment in medical and scientific history. The demonstration that an extract of dog pancreas reproducibly lowered blood glucose, initially in diabetic dogs and then in humans with type 1 diabetes, was a medical breakthrough that changed the course of what was until then a largely fatal disease. The discovery of the "activity", soon named "insulin", was widely celebrated, garnering a Nobel Prize for Banting and McLeod in 1923. Over the ensuing 100 years, research on insulin has advanced on many fronts, producing insights that have transformed our understanding of diabetes and our approach to its treatment. SCOPE OF REVIEW: This paper will review research on insulin that had another consequence of far broader scientific significance, by serving as a pacesetter and catalyst to bioscience research across many fields. Some of this was directly insulin-related and was also recognized by the Nobel Prize. Equally important, however, was research stimulated by the discovery of insulin that has profoundly influenced biomedical research, sometimes also recognized by the Nobel Prize and sometimes without this recognition. MAJOR CONCLUSIONS: By reviewing some of the most notable examples of both insulin-related and insulin-stimulated research, it becomes apparent that insulin had an enormous and frequently under-appreciated impact on the course of modern bioscience.

Is France Once Again Looking for a Scapegoat?

On September 10, 2021, a special tribunal established by the French government launched an inquiry into the activities of former health minister Dr. Agnes Buzyn who was charged with "endangering the lives of others". It is surprising to learn of this accusation and inquiry into the actions of a public health official whose response to the epidemic was, to all appearances, exemplary.

Might ß3-adrenergic receptor agonists be useful in disorders of glucose homeostasis?

Brown and beige adipose tissues contain thermogenic fat cells that can be activated by ß3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O'Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved ß3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that ß3 agonists could have therapeutic utility in disorders of glucose homeostasis.

The US Health Provider Workforce: Determinants and Potential Paths to Enhancement.

The health provider workforce is shaped by factors collectively influencing the education, training, licensing, and certification of physicians and allied health professionals, through professional organizations with interlocking and often opaque governance relationships within a state-based licensing system. This system produces a workforce is that is insufficiently responsive to current needs and opportunities, including those created by new technologies. This lack of responsiveness reflects the complex, nontransparent, and cautious nature of the controlling organizations, influenced by the economic interests of the organized professions, which seek protection from competitors both local and international. The first step in addressing this is to comprehensively examine the organizational complexity and conflicted interests within this critical ecosystem. Doing so suggests areas ripe for change, to enhance the health workforce and benefit public health.

Liver-derived FGF21 is essential for full adaptation to ketogenic diet but does not regulate glucose homeostasis.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is expressed in several metabolically active tissues, including liver, fat, and acinar pancreas, and has pleiotropic effects on metabolic homeostasis. The dominant source of FGF21 in the circulation is the liver. OBJECTIVE AND METHODS: To analyze the physiological functions of hepatic FGF21, we generated a hepatocyte-specific knockout model (LKO) by mating albumin-Cre mice with FGF21 flox/flox (fl/fl) mice and challenged it with different nutritional models. RESULTS: Mice fed a ketogenic diet typically show increased energy expenditure; this effect was attenuated in LKO mice. LKO on KD also developed hepatic pathology and altered hepatic lipid homeostasis. When evaluated using hyperinsulinemic-euglycemic clamps, glucose infusion rates, hepatic glucose production, and glucose uptake were similar between fl/fl and LKO DIO mice. CONCLUSIONS: We conclude that liver-derived FGF21 is important for complete adaptation to ketosis but has a more limited role in the regulation of glycemic homeostasis.

Credit and Priority in Scientific Discovery: A Scientist's Perspective.

Credit for scientific discovery plays a central role in the reward structure of science. As the "currency of the realm," it powerfully influences the norms and institutional practices of the research ecosystem. Though most scientists enter the field for reasons other than desiring credit, once in the field they desire credit for their work. In addition to being a source of pleasure, credit and recognition are necessary for successful careers. The consensus among sociologists, philosophers, and economists is that pursuit of credit increases the efficiency of the scientific enterprise. Publishing results in a scholarly journal is the core approach to obtaining credit and priority, and the publishing landscape is undergoing dramatic change. As research groups get larger and more interdisciplinary, and scholarly journals proliferate, allocating credit has become more difficult. Awards and prizes further contribute to credit by recognizing prior attributions and articulating new credit attributions through their decisions. Patents can have a complex relationship to credit, and disputes over authorship and credit are common and difficult to adjudicate. Pathologic pursuit of credit adversely affects the scientific enterprise. Academic institutions assess credit in appointment and promotion decisions, and are best positioned to assume responsibility for addressing problems with the credit ecosystem. Several possible remedies are presented.

Starvation in the Midst of Plenty: Reflections on the History and Biology of Insulin and Leptin.

Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin's discovery rapidly launched a life-saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.

Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet.

OBJECTIVE: Non-alcoholic fatty liver (NAFL) associated with obesity is a major cause of liver diseases which can progress to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) plays an important role in liver metabolism and is also a potential marker for NAFL. Here we aimed to test the effect of FGF21 deficiency on liver pathology in mice consuming a conventional high fat, high sucrose (HFHS) obesogenic diet for up to 52 weeks. METHODS: C57BL6 WT and FGF21 KO mice were fed a conventional obesogenic diet and were evaluated at 16 and 52 weeks. Evaluation included metabolic assessment, liver pathology, and transcriptomic analysis. RESULTS: With consumption of HFHS diet, FGF21 deficient mice (FGF21 KO) develop excess fatty liver within 16 weeks. Hepatic pathology progresses and at 52 weeks FGF21 KO mice show significantly worse fibrosis and 78% of mice develop HCC; in contrast only 6% of WT mice develop HCC. Well differentiated hepatocellular carcinomas in FGF21 KO mice were characterized by expanded hepatic plates, loss of reticulin network, cytologic atypia, and positive immunostaining for glutamine synthetase. Microarray analysis reveals enrichment of several fibroblast growth factor signaling pathways in the tumors. CONCLUSIONS: In addition to attenuating inflammation and fibrosis in mice under a number of dietary challenges, we show here that FGF21 is required to limit the progression from NAFL to HCC in response to prolonged exposure to an obesogenic diet. The induction of hepatic FGF21 in response to the high fat, high sucrose obesogenic diet may play an important role in limiting progression of liver pathology from NAFL to HCC.

Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury.

OBJECTIVE: Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. METHODS: We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). RESULTS: Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber-DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. CONCLUSIONS: Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.

Dealing with Consequences of Irreproducibility and Modifying the Published Literature: Retractions versus Revisions.

One of the barriers to revising the literature when new data are produced, demonstrating the lack of reproducibility of particular published findings, is the stigma associated with the current tools available, most notably the use of retractions. We suggest an additional tool: revisions, which could be linked to prior manuscripts by the original authors and by others (upon peer review). We hope new approaches such as the ability to revise prior reports will help to keep the literature up-to-date and representative of the most complete understanding of an issue.

Categorizing biomedical research: the basics of translation.

As biomedical research has evolved over the past century, the terminology employed to categorize it has failed to evolve in parallel to accommodate the implications of these changes. In particular, the terms basic research and translational research as used today in biomedicine seem especially problematic. Here we review the origins of these terms, analyze some of the conceptual confusions attendant to their current use, and assess some of the deleterious consequences of these confusions. We summarize that the distinction between basic and translational biomedical research is an anachronism. Elimination of this often contentious distinction would improve both the culture and the effectiveness of the scientific process, and its potential benefits to society.-Flier, J. S., Loscalzo, J. Categorizing biomedical research: the basics of translation.

Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice.

OBJECTIVE: We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. METHODS: To test this hypothesis, we measured the response of mice lacking all three ß-adrenergic receptors (ß-less mice) to KD feeding. RESULTS: In contrast to wild-type (WT) controls, ß-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, ß-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of ß-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and ß-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed ß-less mice. CONCLUSIONS: The response of ß-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more ß-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms.