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Oldfield Lab research

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About Professor Brian Oldfield

Professor Brian Oldfield has been an Australian NHMRC Fellow from 1985 to 2019, most of that time as a Principal Research Fellow. He received his PhD from Monash University, trained postdoctorally at McGill University, Montreal and Columbia University, New York before spending formative years at the Howard Florey Institute, Melbourne where he developed his overriding focus on obesity research.

He was recruited to Monash University in 2005 and since then has pursued interests in different aspects of appetite, energy expenditure and body weight control. In addition to his basic science interests he has sought to influence obesity policy and care for those living with obesity through involvement in national and international planning committees and Societies. Notably, he has been President of the Australian and New Zealand Obesity Society (ANZOS), is currently President of the Asia Oceania Association for the Study of Obesity (AOASO) and Vice President of the World Obesity Federation (WOF).


Our research

Current projects

Our lab’s has three major programs centred on metabolic neuroscience that encompass interests in brown fat biology, the neurobiological underpinnings of metabolic surgery and anorexia nervosa. Our current projects all fall within these three programs.

Visit Professor Oldfield's Monash research profile to see a full listing of current projects.

Research activities

A: Brown Fat Biology and its role in the control of body weight

i) Central neural circuits subserving nutrient–activated thermogenesis - the basis of post prandial energy expenditure

One of the most rapidly developing areas of obesity research over the last decade has focussed on the potential of brown adipose tissue (BAT) to elevate energy expenditure and reduce body weight. At the same time, the field has developed to encompass the phenomenon whereby white fat is “browned” creating so called beige fat. A range of environmental, metabolic, medicinal and even surgical perturbations have been implicated in this beiging process that introduces the potential to further elevate the thermogenic capacity of both humans and animals. What has not happened in this renaissance of brown fat biology is a concomitant increase in our understanding the central neural coordination of brown fat activity or even an understanding of what changes when white fat is transformed to a more “brown-like” phenotype. Our lab is essentially interested in this pivotal aspect of BAT function.

This projects tackles one aspect of BAT recruitment, that following nutrient intake which forms the basis of diet induced or post-prandial (meal) thermogenesis.  An understanding of the detail of the brain circuitry involved in nutrient activated thermogenesis will potentially enable a manipulation of this form of energy expenditure and promote better metabolic outcomes. This project aims to evaluate, using complex viral and in vivo chemogenetic and optogenetic techniques in conjunction with “on line” measurement of BAT function, the importance of specific brain relays in postprandial recruitment of BAT.

This figure depicts AAV-mediated technologies used to modulate the activity of neurons in the arcuate nucleus
of the hypothalamus with concurrent measurement of brown adipose tissue temperature in mice.

B: Animal models of bariatric (weight loss) surgery

i) Mechanisms underlying the efficacy of bariatric surgery – the role gut-brain interactions in the recruitment of brown adipose tissue

Currently the only available effective and durable treatment for morbid obesity is bariatric surgery. Vertical Sleeve Gastrectomy (VSG) is the most widely performed bariatric surgery and it confers both significant weight loss and improved glucose regulation. However, it is agreed that there is a need for viable alternative approaches. Bariatric surgery has small, but well established, attendant risks, including elevated morbidity and even mortality, irreversibility, cost, and surgical wait times. There is also a pervasive and justifiable view that extensive resectional surgery is an inappropriate endpoint to combat obesity. To identify alternatives, an understanding of the physiological underpinnings of the efficacy of procedures like VSG is required. The vagus nerve is an important conduit for information transfer between the gut and brain that underpins some of the efficacy of VSG. Our data, derived from a rat model of VSG, indicate that an increase in energy expenditure via brown adipose tissue (BAT) contributes substantially to the weight loss in VSG.

 
 This figure highlights the potential Gut - Brain pathways that may
underpin changes in food intake and energy expenditure following
bariatric surgery.
This figure highlights the neural circuitry that may be responsible for
mediating shifts in energy expenditure in brown fat in response to gut-derived signals.

In the proposed experiments, we aim to establish whether vagal afferent neurons are necessary for the efficacy of the VSG surgery and interrogate the role of these neurons in the mediation of the VSG-induced thermogenic response and promotion of weight loss. This will be accomplished in a number of projects that use cutting edge, optogenetic and chemogenetic approaches.

This figure shows the AAV-mediated strategies that are being utilised to interrogate the role
of the vagus nerve in mediating the positive metabolic outcomes following bariatric surgery.

The potential to not only characterise the basis of the efficacy of VSG, but to identify the means by which it can be enhanced, has the potential to change the way in which this mainstay of obesity treatment is viewed and practiced. An understanding of the essential physiological drivers of the procedure also opens the possibility of mimicking, then exploiting, these mechanisms in a non-surgical medical setting.

ii) The basis of improved glycemic control after bariatric surgery – insights from rodent models

Bariatric surgery has now been accepted as a front-line treatment for type 2 diabetes (T2D) that compares favourably with lifestyle and medicinal interventions. However, the detail of the mechanisms underlying the profound effect of surgery on glucose regulation remains elusive. An understanding of the physiological mechanisms subserving surgical success will allow its replacement with non-surgical approaches - this is the basis of the current application. Our lab has generated preliminary data from a rodent model of vertical sleeve gastrectomy (VSG) which indicates that brown adipose tissue (BAT) is not only necessary for VSG-induced weight loss but is a major contributor to the sequestration of glucose that underpins the improved glucose regulation immediately after VSG. In addition, there is developing evidence that vagal afferent neurons (VANs) are important in relaying sensory information from the gut to the brain to promote the recruitment of BAT. This project aims to understand the nature of changes in glucose regulation following VSG (prior to weight loss), particularly those attributable to effector organs such as BAT. Specifically, this project will evaluate, using in vivo chemogenetic and optogenetic techniques, the extent to which specific vagal afferent neurons contribute to the resolution of T2D after VSG.

C: Rodent models of Anorexia Nervosa used to study pathological weight loss with implications for normal body weight control and related motivated behaviours

i) Biomarkers of vulnerability to pathological body weight loss in a rat model of anorexia nervosa

Anorexia Nervosa (AN) has a mortality rate 12 times higher than the annual death rate from all causes in females aged 15 to 24. Currently, there is no effective treatment for AN, and there is little consensus about the antecedents and triggers that lead to the development of this debilitating disorder. What is becoming apparent is that an interaction between genetic, behavioural and immunological factors may predispose some individuals to AN. The challenge is to take these observations made in humans and rigorously dissect what underlies them in experimental animal models, where predisposing factors can be manipulated in order to interrogate anorexic behaviour. The most well-accepted animal model of AN, known as activity-based anorexia (ABA), exploits the innate motivation of laboratory rats to run in wheels. When rats with access to running wheels are placed on a restricted feeding schedule, there is a paradoxical increase in running activity despite substantially decreased caloric intake, causing a profound reduction in body weight. Our recent work has revealed that nearly one-third of rats are resistant to body weight loss in the ABA paradigm. This under-reported feature of the model, initially seen as an impediment to the generation of “clean” data, we now see as a compelling reason to develop ABA as a translational model of anorexia nervosa. We believe strongly, as do many others, that it is the variability of responses to physiological challenges and the interrogation of the mechanisms that underlie this variability that will inform the development of more effective treatment strategies. This project will focus on identifying biomarkers of vulnerability to ABA and examining their underlying mechanisms with a view to aiding in the early detection and diagnosis of human AN.

ii) Neural circuitry underlying pathological body weight loss in a rat model of anorexia nervosa

Anorexia Nervosa (AN) has a mortality rate 12 times higher than the annual death rate from all causes in females aged 15 to 24. Currently, there is no effective treatment for AN, which is exacerbated by a reticence to appreciate the neurobiological contribution to the disorder. Despite this, brain imaging studies in AN patients reveal an imbalance between neural activity in regions associated with reward and cognition. The challenge in understanding the causes of AN is to take these observations made in humans and rigorously dissect what underlies them in experimental animal models, where brain circuits can be perturbed and anorexic behaviour can be interrogated. The most well-accepted animal model of AN, known as activity-based anorexia (ABA), exploits the innate motivation of laboratory rodents to run in wheels. When rats with access to running wheels are placed on a restricted feeding schedule, there is a paradoxical increase in running activity despite substantially decreased caloric intake, causing a profound reduction in body weight. The focus of this project is on manipulating brain circuits in the ABA model with a view to rescuing animals from debilitating weight loss. We utilise light- and drug-based approaches (known as optogenetics and chemogenetics) to selectively alter the activity of neural pathways in rats exposed to the ABA paradigm.

In the lab, we utilise “pathway-specific chemogenetics” to selectively manipulate the activity of neural circuits and investigate how they impact on behaviour.
This technique relies on the coincident injection of two constructs – a retrogradely transporting Cre vector (infused into a projection field) and
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that are modified G-protein coupled receptors (infused into target region).
We can then turn this pathway on or off in a behaving animal by administering a designer ligand, clozapine-n-oxide (CNO).

Our recent studies confirm that both ventral reward and prefrontal cognitive circuits impact respectively on food intake and excessive exercise, both essential components of pathological body weight loss in the rat model and the human condition.

We always validate DREADD receptor activity to determine the extent by which CNO changes the activity of brain circuits. We can do this
at a “population level” by examining the proportion of DREADD labelled cells that also express Fos (an early marker of neuronal activation)

using immunohistochemistry. We can also do this at the single-cell level, using patch-clamp electrophysiology to record the electrical activity
of DREADD-expressing neurons in real time, and see how activity changes in response to CNO application.

The intention is to extend these discoveries toward a comprehensive framework of emotional and other cognitive brain pathways that control reward and hunger in ABA and ultimately AN. As with all studies using rodent models of human conditions, the goal is to uncover some aspect of brain function that is not only essential to the development of anorexia nervosa but also modifiable. Any such discovery would have a profound impact on the development of novel treatment strategies for a disorder that responds poorly to available therapeutics.


Collaborations

We collaborate with many scientists and research organisations around the world. Some of our more significant national and international collaborators are listed below. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).

Professor Thomas Lutz, Zurich
Professor Walter Kaye, San Diego
Associate Professor Guillaume DeLartigue, Gainsville
Professor York Winter, Berlin
Professor Stephen Simpson, Sydney
Professor Andrew Allen, Melbourne
Professor Matt Watt, Melbourne
Associate Professor Zane Andrews, Melbourne
Professor Maarten Van den Buse, Melbourne
Professor Wendy Brown, Melbourne
Professor Paul Burton, Melbourne


Student research projects

The Oldfield Lab offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short term research opportunities available.

Please visit Supervisor Connect to explore the projects currently available in our Lab.